Abstract：
BACKGROUND: Cirrhotic patients display an increased risk for both bleeding and thrombosis. We investigated platelet activation across Child-Pugh stages (CPSs) and portal hypertension (PH) severity.
METHODS: A total of 110 cirrhotic patients were prospectively included. CPS and hepatic venous pressure gradient (HVPG) were determined. Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa were measured by flow cytometry before/after stimulation with protease-activated receptor (PAR)-1 (thrombin receptor activating peptide, TRAP) and PAR-4 (AYPGKF) agonists, epinephrine, and lipopolysaccharide (LPS).
RESULTS: Platelet count was similar across CPS but lower with increasing PH severity. Expression of P-selectin and activated GPIIb/IIIa in response to TRAP and AYPGKF was significantly reduced in platelets of CPS-B/C versus CPS-A patients (all p < 0.05). Platelet P-selectin expression upon epinephrine and LPS stimulation was reduced in CPS-C patients, while activated GPIIb/IIIa in response to these agonists was lower in CPS-B/C (all p < 0.05). Regarding PH severity, P-selectin and activated GPIIb/IIIa in response to AYPGKF were lower in HVPG ≥20 mmHg patients (both p < 0.001 vs. HVPG < 10 mmHg). Similarly, activated GPIIb/IIIa was lower in HVPG ≥20 mmHg patients after TRAP stimulation (p < 0.01 vs. HVPG < 10 mmHg). The lower platelet surface expression of P-selectin and activated GPIIb/IIIa upon stimulation of thrombin receptors (PAR-1/PAR-4) in CPS-B/C and HVPG ≥20 mmHg patients was paralleled by reduced antithrombin-III levels in those patients (all p < 0.05). Overall, PAR-1- and PAR-4-mediated platelet activation correlated with antithrombin-III levels (p < 0.001).
CONCLUSIONS: Platelet responsiveness decreases with increasing severity of liver cirrhosis and PH but is potentially counterbalanced by lower antithrombin-III levels.
METHODS: A total of 110 cirrhotic patients were prospectively included. CPS and hepatic venous pressure gradient (HVPG) were determined. Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa were measured by flow cytometry before/after stimulation with protease-activated receptor (PAR)-1 (thrombin receptor activating peptide, TRAP) and PAR-4 (AYPGKF) agonists, epinephrine, and lipopolysaccharide (LPS).
RESULTS: Platelet count was similar across CPS but lower with increasing PH severity. Expression of P-selectin and activated GPIIb/IIIa in response to TRAP and AYPGKF was significantly reduced in platelets of CPS-B/C versus CPS-A patients (all p < 0.05). Platelet P-selectin expression upon epinephrine and LPS stimulation was reduced in CPS-C patients, while activated GPIIb/IIIa in response to these agonists was lower in CPS-B/C (all p < 0.05). Regarding PH severity, P-selectin and activated GPIIb/IIIa in response to AYPGKF were lower in HVPG ≥20 mmHg patients (both p < 0.001 vs. HVPG < 10 mmHg). Similarly, activated GPIIb/IIIa was lower in HVPG ≥20 mmHg patients after TRAP stimulation (p < 0.01 vs. HVPG < 10 mmHg). The lower platelet surface expression of P-selectin and activated GPIIb/IIIa upon stimulation of thrombin receptors (PAR-1/PAR-4) in CPS-B/C and HVPG ≥20 mmHg patients was paralleled by reduced antithrombin-III levels in those patients (all p < 0.05). Overall, PAR-1- and PAR-4-mediated platelet activation correlated with antithrombin-III levels (p < 0.001).
CONCLUSIONS: Platelet responsiveness decreases with increasing severity of liver cirrhosis and PH but is potentially counterbalanced by lower antithrombin-III levels.
摘要：
目的：肝硬化患者出血和血栓形成的风险增加。我们调查了Child-Pugh阶段（CPS）和门静脉高压（PH）严重程度的血小板活化。
方法：前瞻性纳入了110例肝硬化患者。确定CPS和肝静脉压力梯度（HVPG）。在用蛋白酶激活受体（PAR）-1（凝血酶受体激活肽，TRAP）和PAR-4（AYPGKF）激动剂，肾上腺素,和脂多糖(LPS)。
结果：整个CPS的血小板计数相似，但随着PH严重程度的增加而降低。与CPS-A患者相比，CPS-B/C患者的血小板中P-选择素和激活的GPIIb/IIIa响应于TRAP和AYPGKF的表达显着降低（所有p<0.05）。CPS-C患者在肾上腺素和LPS刺激下血小板P-选择素表达降低,而响应这些激动剂的活化GPIIb/IIIa在CPS-B/C中较低(均p<0.05)。关于PH严重程度，在HVPG≥20mmHg患者中，对AYPGKF的P-选择素和激活的GPIIb/IIIa较低（p<0.001vs.HVPG<10mmHg)。同样，TRAP刺激后HVPG≥20mmHg患者激活的GPIIb/IIIa较低(p<0.01vs.HVPG<10mmHg)。在CPS-B/C和HVPG≥20mmHg的患者中，在凝血酶受体（PAR-1/PAR-4）刺激后，P-选择素和活化的GPIIb/IIIa的血小板表面表达降低与抗凝血酶-III水平降低平行。这些患者（所有p<0.05）。总的来说,PAR-1和PAR-4介导的血小板活化与抗凝血酶-III水平相关(p<0.001)。
结论：血小板反应性随着肝硬化和PH严重程度的增加而降低，但可能被较低的抗凝血酶-III水平所抵消。
方法：前瞻性纳入了110例肝硬化患者。确定CPS和肝静脉压力梯度（HVPG）。在用蛋白酶激活受体（PAR）-1（凝血酶受体激活肽，TRAP）和PAR-4（AYPGKF）激动剂，肾上腺素,和脂多糖(LPS)。
结果：整个CPS的血小板计数相似，但随着PH严重程度的增加而降低。与CPS-A患者相比，CPS-B/C患者的血小板中P-选择素和激活的GPIIb/IIIa响应于TRAP和AYPGKF的表达显着降低（所有p<0.05）。CPS-C患者在肾上腺素和LPS刺激下血小板P-选择素表达降低,而响应这些激动剂的活化GPIIb/IIIa在CPS-B/C中较低(均p<0.05)。关于PH严重程度，在HVPG≥20mmHg患者中，对AYPGKF的P-选择素和激活的GPIIb/IIIa较低（p<0.001vs.HVPG<10mmHg)。同样，TRAP刺激后HVPG≥20mmHg患者激活的GPIIb/IIIa较低(p<0.01vs.HVPG<10mmHg)。在CPS-B/C和HVPG≥20mmHg的患者中，在凝血酶受体（PAR-1/PAR-4）刺激后，P-选择素和活化的GPIIb/IIIa的血小板表面表达降低与抗凝血酶-III水平降低平行。这些患者（所有p<0.05）。总的来说,PAR-1和PAR-4介导的血小板活化与抗凝血酶-III水平相关(p<0.001)。
结论：血小板反应性随着肝硬化和PH严重程度的增加而降低，但可能被较低的抗凝血酶-III水平所抵消。
