The concept that cirrhosis is associated with hemostasis-related bleeding tendencies is likely no longer valid, and coagulation cascade activation may actually contribute to the development or worsening of liver disease, according to experts who spoke during the Portal Hypertension SIG Program on Sunday.
“Liver diseases are frequently accompanied by substantial change in the hemostatic system,” said Ton Lisman, MD, of University Medical Center Groningen in the Netherlands. These changes include thrombocytopenia and platelet function deficits, low levels of coagulation proteins and inhibitors, and others. However, Dr. Lisman said that the standard use of prothrombin time is problematic in assessing hemostasis in these patients, as it is a test that is only sensitive for pro-coagulant factors.
Though bleeding is a common complication of cirrhosis, Dr. Lisman said that the most common such complication – bleeding varices – is unrelated to hemostasis. Further, reports have proliferated that liver transplant can be performed in patients with thrombocytopenia without any requirement for blood products. “We think this would not be possible in patients who had a true bleeding tendency,” he said. There are also relatively frequent thrombotic complications in patients with cirrhosis, including venous thrombosis, hepatic vascular diseases, coronary events, and intrahepatic thrombosis.
Patients with cirrhosis actually have a number of hypercoagulable features. One is the dysfunction of the protein C system, which includes protein C and protein S. “Congenital deficiencies in either of these proteins are associated with severe thrombotic tendencies,” Dr. Lisman said.
Patients with cirrhosis also have enhanced thrombin generation, indicating a hypercoagulable state. Dr. Lisman’s lab has also found that cirrhosis patients have decreased fibrin clot permeability. With in vitro generated clots, the ability of a liquid to permeate through the fibrin is diminished when cirrhosis is present, which is significant in terms of the ability to deliver substances that could break down that clot.
Further, platelets in these patients are hyperfunctional and circulating in an activated state, Dr. Lisman said. There is also evidence of increased intravascular tissue factor, again contributing to activation of coagulation. “These new insights have consequences for clinical strategies to prevent or treat thrombotic events in cirrhosis,” he said.
There is also emerging evidence that the coagulation cascade actually plays a role in development of liver disease, said Jim Luyendyk, PhD, of Michigan State University. For example, anticoagulation with enoxaparin has been shown to delay decompensation and improve survival in cirrhotic patients, and prothrombotic risk factors including factor V Leiden are associated with an increased risk of fibrosis. There are ongoing trials evaluating the impact of low molecular weight heparin and other anticoagulants on cirrhosis.
The mechanisms whereby coagulation might exacerbate disease involve several targets of thrombin, Dr. Luyendyk said, including protease activated receptors (PAR1) and fibrinogen. Intrahepatic fibrin deposits could lead to platelet aggregation and development of microthrombi, which in turn can lead to hypoxia. The fibrin deposits also play a role in inflammation, and the combination of these effects can lead to cell injury or death and the development of fibrosis or cirrhosis. Those occlusive fibrin deposits are also a logical way to explain the benefits seen with anticoagulants in patients with chronic liver disease, Dr. Luyendyk said.
Though there is less definitive experimental evidence, he added that PAR1 could directly activate stellate cells, which could lead again to the development of fibrosis. “The mechanism whereby coagulation modifies liver disease may be multifactorial, involving both intrahepatic fibrin deposition and intracellular signaling,” Dr. Luyendyk said.