Is chronic liver disease associated with a bleeding diathesis?
It is evident that liver disease may result in substantial changes in the hemostatic system . As elegantly pointed out by Mannucci in the recently published debate with Reverter [2,3], liver disease not only affects pro-hemostatic systems, but also results in changes in antihemostatic systems. The net effect of these hemostatic changes is unclear, but we agree with Mannucci that compensatory mechanisms may very well lead to a more or less (re)-balanced hemostasis. The defects in platelet number and function may be balanced by substantially elevated von Willebrand factor (VWF) levels, and the decreased levels of coagulation factors and inhibitors of fibrinolysis may be balanced by decreased levels of inhibitors of coagulation and pro-fibrinolytic factors.
Solid proof of a true re-balanced coagulation and fibrinolysis is, however, lacking. The study by Tripodi shows thrombin generation to be similar in patients with cirrhosis as compared to controls when thrombomodulin is added to the thrombin generation test . However, as the test was performed in platelet-poor plasma, the effect of the reduced platelet count in the patients on thrombin generation was obscured. Although the thrombin generation test as performed by Tripodi is a more global test of coagulation as compared to routine test such as the prothrombin time (see our contribution to this Forum on ‘Methodological issues with coagulation testing in patients with liver disease’), measurement of thrombin generation in platelet-rich plasma or whole blood would even more closely represent physiological conditions. Similarly, the fibrinolytic balance in patients with cirrhosis is still incompletely investigated. As pointed out by Mannucci, both pro- and antifibrinolytic factors may be decreased in patients with cirrhosis . We recently showed that plasma fibrinolytic potential is similar in patients with cirrhosis as compared to healthy controls, which was ascribed to a concomitant decrease of pro- and antifibrinolytic factors . The assay used in this study has, however, some limitations as platelets are absent in the assay, and exogenously added tissue-type plasminogen activator (t-PA) is used to initiate fibrinolysis. Previous studies using different fibrinolysis tests have shown that hyperfibrinolysis does occur in a majority of patients with severe cirrhosis due to a t-PA/plasminogen activator inhibitor-1 (PAI-1) imbalance, and hyperfibrinolysis was shown to be associated with an increased risk of gastro-intestinal bleeding [6–8]. However, these tests have also important limitations, and the association between hyperfibrinolysis and bleeding may be a reflection of the severity of the disease (reviewed in Lisman et al. ). Assays measuring global coagulation and fibrinolysis are still lacking, and development of these tests (e.g. a recently developed fibrinolysis test employing non-anticoagulated whole blood ) and evaluation of these tests in predicting bleeding risk in patients with cirrhosis is needed before a definite conclusion can be drawn that disturbances of coagulation and fibrinolysis in patients with cirrhosis do not contribute to bleeding, as stated by Mannucci.
Although Reverter points out the potential occurrence of bleeding complications in patients with liver disease , many of these bleeding problems are not life-threatening but still may be of concern (e.g. bruising, petechiae, purpura, nose bleeds, and bleeding after dental extractions). However, the clinically most relevant bleeding problems in these patients, bleeding from ruptured esophageal varices, is a consequence of local vascular abnormalities as well as increased splanchnic blood pressure, and the role of deranged hemostasis in variceal bleeding is questionable .
One of the most evident hemostatic challenges for a patient with chronic liver failure is liver transplantation. Liver transplantation is a lengthy procedure with extensive surgical wound surfaces including potential transection of collateral veins. In the past, liver transplantation required extensive blood product transfusion, which was ascribed to pre- and perioperative hemostatic dysfunction . However, nowadays blood loss during transplantation is often rather limited for a procedure with such surgical invasiveness. Transfusion requirements have dropped to a median of 2–3 U of red blood cells in many centers, and a substantial number of patients (up to 50%, depending on the center) are transplanted without the need of any transfusion . One recent study even reported that 79% of a series of almost 100 patients could be transplanted without the use for any blood products, provided the patient's central venous pressure was controlled through restriction of volume replacement, elimination of all plasma transfusion, and by using intra-operative phlebotomy during the transplantation .
As increasing surgical experience, improvements in surgical techniques, and improvement of anesthesiological care have led to this marked reduction of blood loss during liver transplantation, it has to be concluded that liver disease is not essentially associated with a severe coagulopathic state in this situation. A procedure with these surgical characteristics could never be performed without prophylaxis or transfusion requirements in a patient with an established (classical) coagulopathy, for example, a patient with hemophilia. These observations can be explained best by the presence of compensatory mechanisms (e.g. low levels of coagulation inhibitors and fibrinolytic activators, and high levels of VWF) in patients with chronic liver failure. Nonetheless, there remains the acute or chronic compensated liver failure patient with severe and refractory bleeding. The main question arising from these observations is: how can we detect patients at risk for severe bleeding with available testing? In our opinion, which we will substantiate in our other contributions to this forum, in current times, we do not have a readily available laboratory test that is capable of stratifying bleeding risk in these patients.