Prolonged bleeding time in experimental cirrhosis: role of nitric oxide

C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.Bhatal et al. first showed in in-vitro perfused cirrhotic rat livers, that nitroprusside and papaverine reduced portal resistance up to 15%. This change represents up to 28% of the magnitude by which the IHVR of the cirrhotic liver exceeds that of normal livers. 1 Interestingly the magnitude of effect in the diseased liver seems to be similar for different vasodilators, whereas it is almost negligible in the normal liver. 2 This difference shows the presence of an enhanced intrinsic vascular tone in the intrahepatic microvascular bed of the cirrhotic liver that is not present in nondiseased livers.For years, nitrovasodilators were in clinical use as vasorelaxants before a mechanism of action was uncovered. Investigators identified nitric oxide (NO), an endothelium-derived relaxing factor, in 1987. 3 It is now established that NO is a key factor in the hemodynamic abnormalities associated with liver cirrhosis and chronic portal hypertension. Owing to the lack of a basement membrane and to the presence of fenestrae, sinusoidal endothelial cells are anatomically and biologically distinct from endothelial cells in other vasculature. They are, however, similar to other endothelial cells in that they produce and release NO. 4 By means of sinusoidal and other endothelial cells, the liver modulates local intrahepatic vascular tone and resistance and determines the physiological adaptation or pathophysiological dysfunction of the intrahepatic microcirculation.Under physiologic and tightly regulated conditions, nitric oxide synthases (NOS) generate NO. Alterations in the synthesis of NO, which is seen in cirrhosis, may therefore form a basis for future developments in its therapy. Furthermore, the development of optimal potential therapy is dependent on a detailed knowledge of the chemistry and metabolism of NO, and especially the diverse effects it induces. Therefore, the purpose of this review is to (1) summarize the chemical reactions in which NO participates and the effects mediated by those reactions, (2) give a short overview of the regulation of NOS, and (3) to outline the available data and current concepts regarding the involvement of NO in the hemodynamic abnormalities associated with liver cirrhosis. By no means, in this review, are we denying the participation of other mediators not only in the increased intrahepatic vascular resistance (e.g., endothelins) but also in the vasodilatation and hyperdynamic state observed in the splanchnic (e.g., anandamide) and systemic circulation (e.g., sodium and water retention). However, the focus of this review is NO.

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“…Indeed, inhibition of NO synthesis in experimental cirrhosis normalizes the prolonged bleeding time. 161 …”

Section: Systemic and Splanchnic No Overproductionmentioning

confidence: 99%

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

2002

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“…This hyperdynamic state, in which nitric oxide (NO) and prosatcyclin (PGI2) are important vasoactive substances, induces a decreased platelet activity, even in the absence of hepatic damage. Although NO plays an important role in modifying platelet adhesion in portal hypertension [2] , PGI2, a powerful vasodilator prostanoid with antithrombotic properties, was also found increased in mesenteric vascular bed [3] . Ultra low dose aspirin (ULDA) has shown prothrombotic activity when analysed in humans and in the interface platelet-endothelial cell [4,5] .…”

Section: Introductionmentioning

confidence: 99%

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Eizayaga

Aguejouf²,

Desplat³

et al. 2007

WJG

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INTRODUCTIONPortal hypertension is a major complication of chronic liver disease. In its pathophysiology, increased hepatic resistance is followed by a hyperdynamic circulatory state [1] . This hyperdynamic state, in which nitric oxide (NO) and prosatcyclin (PGI2) are important vasoactive substances, induces a decreased platelet activity, even in the absence of hepatic damage. Although NO plays an important role in modifying platelet adhesion in portal hypertension [2] , PGI2, a powerful vasodilator prostanoid with antithrombotic properties, was also found increased in mesenteric vascular bed [3] . Ultra low dose aspirin (ULDA) has shown prothrombotic activity when analysed in humans and in the interface platelet-endothelial cell [4,5] . Previous papers have shown the potentially beneficial effect of ULDA in portal hypertensive animals normalizing altered platelet activity and induced hemorrhagic time [6] . Further experiments were performed to clarify if this effect was mediated mostly by a cyclooxigenase (COX) pathway or by modifying NO synthesis, the two aspirin mechanisms of action [7] , although a previous study with a different model suggested that ULDA could decrease PGI2 synthesis [8] . The same in vivo Laser induced thrombus formation, was used in portal hypertensive rats to investigate the effects of Indomethacin, a non selective COX inhibitor, and L-Nitro Arginin Methyl Ester (NAME), a non selective inhibitor of NO production. The results suggested that the effects of ULDA were more influenced by COX pathway than by NO synthesis inhibition [9] . Addition of ULDA in portal hypertensive rats, when previously inhibiting COX with Indomethacin, increased number of emboli and duration Abstract AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS:Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1α, TXB2, PGE2 and LTB4 were also performed. RESULTS:The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1α was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION:These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2

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“…To investigate the mechanisms responsible for defective platelet activation we first examined the levels of the stable NO metabolites nitrate and nitrite by ELISA, because it is known that cholestasis induces altered nitric oxide (NO) metabolism [18]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Impaired platelet activation and adhesion might be due to defective signal transduction in platelets from cirrhotic patients, an acquired storage pool deficiency [15] and decreased concentration of arachidonic acid that is important for thromboxane A2 production [16]. Furthermore, increased levels of cyclic nucleotides [17] and nitric oxide (NO) [18] might account for impaired platelet function in patients with liver failure.…”

Section: Introductionmentioning

confidence: 99%

“…Atucha and colleagues described increased Ca 2+ responses of platelets from bile duct ligated rats [24]. In contrast to these studies showing platelet hyperactivity, hypoaggregability has been proposed from others with reduced expression of P-selectin, defective aggregation and prolonged bleeding times [15, 18, 23, 25]. Effects of bile acids on platelet activation have also been suggested [26].…”

Section: Introductionmentioning

confidence: 99%

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Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

Gowert

Klier

Reich

et al. 2017

Cell Physiol Biochem

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Background/Aims: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. Methods: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice. Results: BDL in mice had a moderate effect on platelet counts; however, intrinsic platelet activation was strongly reduced upon activation of the collagen receptor GPVI at early time points. 7 days after bile duct ligation, platelets displayed an almost complete loss of activation with reduced agonist-triggered release of alpha and dense granules and expression of integrin α_IIbβ₃ on the platelet surface. This activation defects resulted in strongly reduced thrombus formation under flow, reduced platelet adhesion to fibrinogen and bleeding complications in BDL mice as measured by tail bleeding experiments. Mechanistically, elevated nitric oxide and prostacyclin levels induced phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), an established inhibitor of platelet activation. Furthermore increased tissue plasminogen activator in plasma of BDL mice led to enhanced plasmin levels that might be responsible for reduced glycoprotein expression of BDL platelets. Besides, high amounts of bile acids contribute to defective signal transduction as shown in platelets from mice fed with a cholic acid diet. Conclusions: Cholestatic liver disease induces multiple platelet activation defects and impairs thrombus formation responsible for bleeding complications at least in mice.

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Prolonged bleeding time in experimental cirrhosis: role of nitric oxide

Cited by 29 publications

References 17 publications

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

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