Let's start with chronic liver disease and bleeding disorders. And we know that end-stage liver disease often results in bleeding disorders. Liver biopsy has bleeding as a significant risk factor because the liver produces many proteins involved in the calculation. At the same time, the interpretation of clotting laboratory tests is actually is not very straightforward. How to use laboratory diagnostic tests for coagulation correctly in chronic liver disease?

Yes, it is a fact indeed that patients with chronic liver disease do bleed, particularly in the gastrointestinal tract, from esophageal varices. It is also true that patients may bleed, but very rarely, I would say, at the time of a closed procedure, such as a liver biopsy. Another fact, indeed, is that patients have an abnormal coagulation test, particularly an abnormally prolonged prothrombin time. However, and this is the main point that I want to convey, patients also have decreased coagulation factors reflected in the propagation of the prothrombin time. But patients also have a decrease in the naturally occurring anticoagulant proteins like antithrombin, protein C, and protein S because, like the coagulation factors, they are produced by the liver. So altogether, there is a rebalancing of their coagulation at a lower level, but there is a rebalance. In other words, they do not bleed because of the abnormal prothrombin time and other tests. So these tests are of little use to predict whether or not the patient with liver disease with bleed. It's so little use to correct this test to prevent this bleeding. A patient with liver disease bleeds mainly the GI tract for reasons other than their coagulation defects. I repeat, it is compensated by the effect of the naturally occurring anticoagulants. Patients with liver disease bleed because of portal hypertension. In the gastrointestinal tract, there is hypertension. Patients bleed because of varices that occur in the stomach and in the duodenum area. So that is what I wanted to say. There is a tendency to bleed but the tendency to bleed is not predicted nor associated with the abnormality in the coagulation tests. They are rebalanced by the naturally occurring anticoagulants.

So what are the correct diagnostic tests to detect a risk of bleeding? How to interpret them for a patient who might have chronic liver disease? How to assess the risks of bleeding? How can clinical physicians assess the risks of bleeding? Or what should they do?

The coagulation tests are useful. But they are useful to establish the degree of dysfunction of the liver. So the prothrombin time is still a similar test. It is very useful to establish the degree of liver insufficiency. But it does not predict the tendency to bleed. So from that point of view, coagulation tests are quite useless. And the prevention of bleeding is associated with other measures, such as the decrease of portal hypertension, with beta-blockers, or with the ligation of varices. Bleeding risk is decreased with measures that address portal hypertension, not abnormal coagulation.

Right! So portal hypertension is something that physicians should look in a patient with a chronic or end-stage liver disease.

That is the main culprit.

What are the implications of coagulation abnormalities in end-stage and chronic liver disease for the treatment and prognosis of the patients?

The implication for the prognosis is that coagulation tests evaluate liver function. And so, the more abnormal are the coagulation tests, particularly the time-honored prothrombin time, the more likely is the patient to have problems and perhaps also to die. So coagulation tests predict severity and death, But they don't predict the onset or the severity of bleeding. So they are useful, but they are only limited. They don't predict the bleeding tendency.

Are there any specific metrics for assessing prothrombin time and trying to predict the necessity for liver transplantation or any other major interventions that have to be done on the patient? Of course, it does depend upon the primary underlying cause of the liver problem. But are there any predictive factors that can be used? Prothrombin time, for example.

The prothrombin time is one of the tests used to evaluate the severity of the liver disease. It is included in the score that evaluates the need for liver transplantation. Then, of course, when this is done and the liver is transplanted, the prothrombin time becomes normal. So, there is a very marked amelioration of the coagulation test abnormalities and also of the bleeding tendency. But it is not because there is a correction of the abnormal coagulation. But because there is a correction through the transplanted liver of portal hypertension.