Altered platelet function in cirrhosis of the liver: Impairment of inositol lipid and arachidonic acid metabolism in response to agonists

Abstract

Hemorrhagic disorders are common in patients with liver cirrhosis and result from several factors including impaired platelet function. We evaluated platelet aggregation and arachidonic acid metabolism in response to standard agonists in platelet-rich plasma from 12 cirrhotic patients with mild impairment of liver function (Child A), 12 patients with severe liver dysfunction (Child B and C) and 12 healthy subjects. Platelet aggregation and thromboxane A2 production were consistently reduced in patients with severe liver impairment. To determine whether the platelet dysfunction is due to an intrinsic platelet defect or a circulating inhibitor, we measured platelet aggregation and thromboxane A2 synthesis on washed platelets in healthy subjects and in Child B and C patients. The aggregating response of washed platelets in response to thrombin, collagen and arachidonic acid was markedly reduced, suggesting an intrinsic platelet defect. The biochemical events underlying platelet aggregation were investigated by prelabeling platelets with [1-14C]arachidonic acid. Thrombin-induced activation of phospholipase C (measured as the release of [1-14C]phosphatidic acid) and phospholipase A2 (measured as the release of [1-14C]arachidonic acid and its metabolites) was greatly impaired in platelets from patients with severe liver impairment. We conclude that in advanced cirrhosis there is a severe reduction in platelet aggregatory response to physiologic agonists due to an intrinsic platelet defect which is related to an impairment of the platelet transmembrane signaling mechanism induced by receptor stimulation.

Thrombin generation in patients with cirrhosis: The role of platelets

“…14,15 A complex defect has been described that ranges from an impaired synthesis of thromboxane A2 and defective signal transduction to the presence of storage pool disease and defects of glycoprotein Ib. [16][17][18][19][20][21] However, the contribution of each of these defects to the hemostatic derangement in patients with cirrhosis has not been fully elucidated. Platelets support hemostasis in vivo through a dual mechanism.…”

Posterior Reversible Encephalopathy Syndrome after Solid Organ Transplantation

“…61 Patients are intrinsically immunocompromised with low albumin, hepatic failure, and an underlying coagulopathy (intrinsic platelet dysfunction, platelet consumption [splenomegaly], and inadequate coagulation factors). [61][62][63] The surgical procedure is technically complex with a mandatory "no-turning-back" point (major vessels clamped, bypass established, recipient liver removed), significant blood and fluid shifts, and intrinsic coagulopathy. 64 The immediate period after liver transplantation (0 -3 months) is challenging, with a high risk for infection (bacterial, viral, or fungal) and cardiovascular instability (hypotension: exaggerated venous capacitance [varices], low albumin, operative blood and fluid loss) and intrinsic immunosuppression.…”

Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged

“…Furthermore, for various reasons (see [2] for review), patients with chronic liver disease are also thrombocytopenic. Platelet dysfunctions have also been reported in a number of studies that may also contribute to the defective platelet adhesion and aggregation [3][4][5][6][7][8][9][10][11]. These observations have over the years made out chronic liver disease to be the epitome of acquired hemostasis deficiency including abnormalities of primary hemostasis, coagulation and fibrinolysis.…”