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160 Inherited coagulation disorders in cirrhotic patients with and without portal vein trhombosis (PVT)
Category 2a." Cirrhosis and Complications." Pathophysiology suggesting h3Toreactivity, while the CBDLoctreo group had a normal MBF response, which was not different from both sham groups. Conclusion: This in vivo study demonswates an impaired response to endothelium-dependent and endothelium-independent vasodilators in the mesenteric artery of experimental animals with cirrhosis. This hyporeactivity is prevented and/or restored by the early administration of octreotide LAR. This suggests an abnormality in the vascular smooth muscle cells o f the mesenteric artery, which can be influenced by octreotide. Administration of octreotide was able to normalise arterial blood pressure and tended to decrease MBF in cirrhotic rats. Further study to explore the possible beneficial effect of acute administration of octreotide or sornatostatin on splanchnic and systemic hemodynamics should be performed.
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HYPORESPONSIVENESS OF ERYTHROCY-rES ~2-ADRENOCEPTORS IN PATIENTS WITH CIRRHOSIS AND PORTAL HYPERTENSION
EZ Hernfindez2, R Zapatet 2, E. De Madarial., J.M. Palaz6n 1, J. Irurzun 3, S. Pascual I , J. Such 1, J.E Horga 2, M. P~:ez-Mateo I . :Unidad Hepdtica,
Hospital General Universitario de Alic'ante, Alicante, Spain; 2Unidad de Farmacologia Cllnica, Hospital General Universitario de Alicante, Alicante, Spain," ~Unidad de Radiologia Vascular Interoencionista, Hospital General Universitario de Alicante, Alicante, Spain Introduction: Patients with cirrhosis are characterized by a hyperldnetic circulation with low arterial pressure and hyporesponsiveneas to adrenergic vasoconstrictors. In these patients, endothelium-free hepatic and mesenteric arteries are hyporeactive to 0~-1 and 13-2 adrenoceptor agonists. We have investigated the functional status of 13-2 adrenoceptors/adenylate cyclase (AC) system in these patients. Methods: the AC activity before and after a stimulus with tile beta agonist isoproterenol was evaluated determining the c~a3MP production in erythrocyte membranes from patients with cirrhosis, portal hypertension and oesophageal varices at baseline (n 39) and after three months of oral treatment with propranolol (n 18). Blood samples from 11 h e a l @ volunteers were used as controls. Data are expressed as mean±SD. Differences between groups were analysed using the Mann-Whimey U-test and the Wilcoxon signed-rank test for paired data. A two-tailed P below 0.05 was considered statistically significant. Results: Patients showed a higher basal AC activity than controls before (46.1±45.3 vs 5.8±7.1pmol/mg prot.; p 0.01) and after treatrnent with propranolol (37.5±37.3pmol/mg prot.; p 0.006). Isoproterenolol increases the AC activity in 10 controls compared with only 19 patients at baseline (91 vs 49%; p=0.02) and 11 patients after propranolol treatment (91 vs 61%; p 0.1). Rise in AC activity induced by isoproterenol was similar in controls (28.8±23.8 pmol/mg prot), patients at baseline (32.1±44.6 pmol/mg prot) and patients after propranolol (23.3±22.8pmol/mg prot). Responders patients to isoproterenol had lower wedged hepatic venous pressure (22.8± 1.2 vs 26.9--1.7 mmHg; p 0.01) and hepatic venous pressure gradient (16.2±0.7 vs 19.4±l.2mmHg; p= 0.02). After three months of propranolol, responders to isoproterenol showed a higher free hepatic venous pressure (7.9±1.9 vs 5.2±1.9; p = 0.04) and lower hepatic venous pressure gradient than non-responders (14.0±4.6 vs 15.8±4.3; p=0.43). Conclusions: patients with cirrhosis and portal hypertension have a higher basal AC activity and a loss of 13-adrenergic function compared with control. Wedged and free hepatic venous pressure and the gradient were different between responders and non-responders to isoproterenol, suggesting a posible relationship between 13-adrenoceptors alterations and haemodynamical changes in patients with portal hypertension.
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65
INHERITED COAGULATION DISORDERS IN CIRRHOTIC PATIENTS WITH AND WITHOUT PORTAL VEIN TRHOMBOSIS (PVT)
A. De Santis I , E Cristofari I , F. Oigliotti I , S. Trapani I , R. Moscatelli I , L. Conti 2, E Guadagni 2, A. Magnapera 2, A.E Attili 1 . 1Department of
Clinical Medicine, La Sapienza University, Rome, Italy," 20ncological Institute, Regina Elena Hospital, Rome, Italy Background and Aims: PVT is an event that frequently complicates cirrhosis. In our cirrhotic patients the frequency of PVT was 26%. Recently, new inherited thrombophilic disorders such as Factor V Leiden (FVL), mutation G20210A of prothrombin (PTHRG20210A), mutation T677 of methylenetetrahydrofolate reductase (MTHFRT677) and allele 4G of plasminogen activator inhibiter-1 (PAI-1) have been identified and associated with an increased risk of venous thrombosis. The aims of our study were to investigate the role of thrornbophilic disorders in the pathogenesis o f PVT in cirrhotic patients. Material and Methods: We enrolled 87 patients (49 M and 38 F), mean age 61.8+10.9yrs, Child-Pugh Class A n = 3 7 , B n = 4 0 , C n = 10, with histolo~cal or clinical diagnosis of cirrhosis. All patients underwent an upper abdominal ultrasound examamination with color and power Doppler evaluation of portal tree with a Sonoline Antares equipment (Siemens Medical Solutions USA Inc., Issaquah, WA). A blood sampling was obtained to assess the prevalence of FVLG1691A and H1299R, PTHRG20210A, MTHFRT677and A1298C, PAI-1 allele 4G in patients with and without PVT. A questionnaire, investigating previous venous thrombosis and familiarity for these events, was also completed. Results: The prevalence of PVT was 19.5%. A previous venous thrombosis was more frequent, but not significantly, in patients with PVT: 23.5% vs 8.7%, p 0.08). A heterozygous FVLG1691A was significantly more frequent in patients with PVT: 11.8% vs 1.4% (p=0.036). In all these cases a resistance to activated protein C was present. The prevalence FVLH1299R, PTHRG20210A, MTHFRT677 and A1298C, PAI-1 4G allele was similar in both groups of patients. The mean values of homocysteine were 10.2+1.9 and 11.3+4.6~/.mol/1, in patients with and without PVT, respectively. Conclusions: In our study only FVLG1691A is more frequent in patients with PVT, while we have not found any association between PTHRG20210A, MTHFRT677 and A1298C, allele 4G of PAI-1, contrary to that found in the literature.
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INCREASED URINARY EXCRETION OF APELIN IN CIRRHOTIC RATS WITH ASCITES. RELATIONSHIP WITH RENAL EXCRETORY FUNCTION
G. Fernandez-Varo 1 J. Ros 1, P. Melgar 1, J. Mufioz-LuqueI , V Arroyo 2, J. Rodes 2, W. Jimenez I . :Hormonal Laboratory, Hospital CBnic
Universitari, Institut d'lnvestigacions Biom~diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain," 2Liver Unit Institut de Malalties Digestives, Hospital Clinic Universitari, Institut d'Investigacions Biom~diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain Background and Aims: Apelin is a 36-aa peptide derived from the 77aa precursor prepoapelin, which has been cloned in humans and rats. This peptide has recently been identified as tile endogenous ligand for the previous orphan Apelin-Angiotensin receptor-like 1, also known as the AJP receptor. Apelin is a potent diuretic neuropeptide that counteeacts vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release and that promotes in vivo inotropic effects on normal and failing hearts. In the present study the urinary excretion of apelin was measured in cirrhotic rats with ascites with and without water retention and in control rats to assess whether apefin participates in the regulation of sodium and water excretion in cirrhosis.
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HYPORESPONSIVENESS OF ERYTHROCY-rES ~2-ADRENOCEPTORS IN PATIENTS WITH CIRRHOSIS AND PORTAL HYPERTENSION
EZ Hernfindez2, R Zapatet 2, E. De Madarial., J.M. Palaz6n 1, J. Irurzun 3, S. Pascual I , J. Such 1, J.E Horga 2, M. P~:ez-Mateo I . :Unidad Hepdtica,
Hospital General Universitario de Alic'ante, Alicante, Spain; 2Unidad de Farmacologia Cllnica, Hospital General Universitario de Alicante, Alicante, Spain," ~Unidad de Radiologia Vascular Interoencionista, Hospital General Universitario de Alicante, Alicante, Spain Introduction: Patients with cirrhosis are characterized by a hyperldnetic circulation with low arterial pressure and hyporesponsiveneas to adrenergic vasoconstrictors. In these patients, endothelium-free hepatic and mesenteric arteries are hyporeactive to 0~-1 and 13-2 adrenoceptor agonists. We have investigated the functional status of 13-2 adrenoceptors/adenylate cyclase (AC) system in these patients. Methods: the AC activity before and after a stimulus with tile beta agonist isoproterenol was evaluated determining the c~a3MP production in erythrocyte membranes from patients with cirrhosis, portal hypertension and oesophageal varices at baseline (n 39) and after three months of oral treatment with propranolol (n 18). Blood samples from 11 h e a l @ volunteers were used as controls. Data are expressed as mean±SD. Differences between groups were analysed using the Mann-Whimey U-test and the Wilcoxon signed-rank test for paired data. A two-tailed P below 0.05 was considered statistically significant. Results: Patients showed a higher basal AC activity than controls before (46.1±45.3 vs 5.8±7.1pmol/mg prot.; p 0.01) and after treatrnent with propranolol (37.5±37.3pmol/mg prot.; p 0.006). Isoproterenolol increases the AC activity in 10 controls compared with only 19 patients at baseline (91 vs 49%; p=0.02) and 11 patients after propranolol treatment (91 vs 61%; p 0.1). Rise in AC activity induced by isoproterenol was similar in controls (28.8±23.8 pmol/mg prot), patients at baseline (32.1±44.6 pmol/mg prot) and patients after propranolol (23.3±22.8pmol/mg prot). Responders patients to isoproterenol had lower wedged hepatic venous pressure (22.8± 1.2 vs 26.9--1.7 mmHg; p 0.01) and hepatic venous pressure gradient (16.2±0.7 vs 19.4±l.2mmHg; p= 0.02). After three months of propranolol, responders to isoproterenol showed a higher free hepatic venous pressure (7.9±1.9 vs 5.2±1.9; p = 0.04) and lower hepatic venous pressure gradient than non-responders (14.0±4.6 vs 15.8±4.3; p=0.43). Conclusions: patients with cirrhosis and portal hypertension have a higher basal AC activity and a loss of 13-adrenergic function compared with control. Wedged and free hepatic venous pressure and the gradient were different between responders and non-responders to isoproterenol, suggesting a posible relationship between 13-adrenoceptors alterations and haemodynamical changes in patients with portal hypertension.
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65
INHERITED COAGULATION DISORDERS IN CIRRHOTIC PATIENTS WITH AND WITHOUT PORTAL VEIN TRHOMBOSIS (PVT)
A. De Santis I , E Cristofari I , F. Oigliotti I , S. Trapani I , R. Moscatelli I , L. Conti 2, E Guadagni 2, A. Magnapera 2, A.E Attili 1 . 1Department of
Clinical Medicine, La Sapienza University, Rome, Italy," 20ncological Institute, Regina Elena Hospital, Rome, Italy Background and Aims: PVT is an event that frequently complicates cirrhosis. In our cirrhotic patients the frequency of PVT was 26%. Recently, new inherited thrombophilic disorders such as Factor V Leiden (FVL), mutation G20210A of prothrombin (PTHRG20210A), mutation T677 of methylenetetrahydrofolate reductase (MTHFRT677) and allele 4G of plasminogen activator inhibiter-1 (PAI-1) have been identified and associated with an increased risk of venous thrombosis. The aims of our study were to investigate the role of thrornbophilic disorders in the pathogenesis o f PVT in cirrhotic patients. Material and Methods: We enrolled 87 patients (49 M and 38 F), mean age 61.8+10.9yrs, Child-Pugh Class A n = 3 7 , B n = 4 0 , C n = 10, with histolo~cal or clinical diagnosis of cirrhosis. All patients underwent an upper abdominal ultrasound examamination with color and power Doppler evaluation of portal tree with a Sonoline Antares equipment (Siemens Medical Solutions USA Inc., Issaquah, WA). A blood sampling was obtained to assess the prevalence of FVLG1691A and H1299R, PTHRG20210A, MTHFRT677and A1298C, PAI-1 allele 4G in patients with and without PVT. A questionnaire, investigating previous venous thrombosis and familiarity for these events, was also completed. Results: The prevalence of PVT was 19.5%. A previous venous thrombosis was more frequent, but not significantly, in patients with PVT: 23.5% vs 8.7%, p 0.08). A heterozygous FVLG1691A was significantly more frequent in patients with PVT: 11.8% vs 1.4% (p=0.036). In all these cases a resistance to activated protein C was present. The prevalence FVLH1299R, PTHRG20210A, MTHFRT677 and A1298C, PAI-1 4G allele was similar in both groups of patients. The mean values of homocysteine were 10.2+1.9 and 11.3+4.6~/.mol/1, in patients with and without PVT, respectively. Conclusions: In our study only FVLG1691A is more frequent in patients with PVT, while we have not found any association between PTHRG20210A, MTHFRT677 and A1298C, allele 4G of PAI-1, contrary to that found in the literature.
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INCREASED URINARY EXCRETION OF APELIN IN CIRRHOTIC RATS WITH ASCITES. RELATIONSHIP WITH RENAL EXCRETORY FUNCTION
G. Fernandez-Varo 1 J. Ros 1, P. Melgar 1, J. Mufioz-LuqueI , V Arroyo 2, J. Rodes 2, W. Jimenez I . :Hormonal Laboratory, Hospital CBnic
Universitari, Institut d'lnvestigacions Biom~diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain," 2Liver Unit Institut de Malalties Digestives, Hospital Clinic Universitari, Institut d'Investigacions Biom~diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain Background and Aims: Apelin is a 36-aa peptide derived from the 77aa precursor prepoapelin, which has been cloned in humans and rats. This peptide has recently been identified as tile endogenous ligand for the previous orphan Apelin-Angiotensin receptor-like 1, also known as the AJP receptor. Apelin is a potent diuretic neuropeptide that counteeacts vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release and that promotes in vivo inotropic effects on normal and failing hearts. In the present study the urinary excretion of apelin was measured in cirrhotic rats with ascites with and without water retention and in control rats to assess whether apefin participates in the regulation of sodium and water excretion in cirrhosis.