Adequate levels of clotting factors, regulatory proteins and platelets help achieve optimal clot formation, clot limitation, and dissolution in normal healthy individuals. However, the same is not the case in patients with liver disease who often present with an imbalance in the levels of pro-coagulant and anticoagulant factors and, hence, face difficulties in the normal coagulation cascade.

Coagulation disorders are commonly seen in the management of clinical scenarios such as esophageal variceal bleeding, invasive and percutaneous procedures, portal vein thrombosis, venous thromboembolism, and acute liver failure in gastroenterology. There are no established laboratory tests that accurately reflect the changes in both the pro-coagulant and anticoagulant systems and, hence, routine laboratory testing in the background of liver disease may delude the clinician and prompt inappropriate therapies with little real benefit.

This article aims to provide an overview on the current understanding of hemostasis in chronic liver disease, its laboratory abnormalities, and the strengths and weaknesses of current testing and treatment strategies in common clinical scenarios.

The clotting process is a dynamic cascade of multiple complex processes involving the endothelium, coagulation factors, and platelets?with the ultimate goal of reducing the loss of blood at the site of an injury and laying the basis for injury repair and healing.

The following mechanisms have been proposed in its pathophysiology:

As per this theory, hemostasis is a cellular process with the activated platelet as the primary effector cell and enabler of coagulation. The clot is basically a platelet plug restrained by a fibrin mesh formed by the conversion of fibrinogen to fibrin by the enzyme thrombin.

The process involves three phases: (1) primary hemostasis or the initial plugging of the vascular breach by activated platelets; (2) coagulation, fibrin mesh construction, and clot fortification by the plasma pro-coagulant proteins; and once vascular repair is complete, (3) fibrinolysis or breakdown of the fibrin mesh by plasma anticoagulant proteins (see the figure below).

The global effect of liver disease on hemostasis is complex and can lead to either a bleeding diathesis or excessive clot formation, with changes in all phases of hemostasis caused by hepatic synthetic dysfunction and portal hypertension (with portosystemic shunting and endothelial dysfunction).

Compensatory mechanisms help in rebalancing of the coagulation system in patients with liver disease. Synthetic dysfunction and impaired protein production that occurs in both pro-coagulant and anticoagulant proteins and leads to a counterbalancing effect on each other is one such example.

Hence, the patient with advanced liver disease remains in a relatively balanced state of hemostasis and would uncommonly experience spontaneous bleeding or clotting unless provoked by another specific trigger.

The primary abnormality in chronic liver disease patients is a decrease in the circulating platelet count. Studies on comparison of platelets from cirrhosis patients to healthy controls show that a level of around 50-60-109/L is the relative limit for adequate thrombin generation, and levels above 100-109/L show little extra benefit compared with controls.

The etiology is believed to be multifactorial with pooling of platelets and sequestration in the spleen and a minor contribution by immunologic mechanism in the form of antiplatelet glycoprotein IIb-IIIa antibodies in cirrhosis patients.

Some conflicting evidence exists for the qualitative defect in platelet function in liver disease. Endothelial dysfunction levels of the von Willebrand factor (vWF), a factor that largely mediates platelet adherence to the endothelial surface, are elevated in proportion to the severity of liver disease..

Liver disease, especially cirrhosis, is characterized by reduced synthesis of the pro-coagulant proteins II, VII, IX and X, as well as factor V and factor XI. This leads the clinician to believe that there is a high risk of bleeding that is due to coagulation protein deficiencies. However, studies show that this may be a misconception.

In spite of the decreased levels of pro-coagulant factors and abnormal international normalized ratio (INR) measurements, cirrhotic patients do not typically have spontaneous bleeding in specific sites like patients with congenital clotting factor deficiencies (e.g., hemarthroses).

This normal clotting potential is largely due to a decrease in synthesis of a potent anticoagulant protein C, coupled with increased endothelial-derived factor VIII, which substantiates that patients with liver disease have a counterbalancing effect. However, small disturbances in this rebalancing effect may predispose a liver disease patient to bleeding or clotting. With the progression of disease, the activity of the pro-coagulant proteins drops to as low as 20-46%.

These tendencies to clotting or bleeding are not static and are largely dependent on the clinical status of the patient. Acute events such as infection, variceal bleeding, and uremia lead to sharp changes in the coagulation cascade in patients with liver disease. They are partially reversible with proper treatment but are not well recognized on conventional tests such as the INR, making it a clinical challenge to spot them at the right time before an event (bleeding or clotting) occurs.

The common lab tests available only give information on small parts of the coagulation system and there is a lack of comprehensive tests to show the complete picture in an individual patient.

The table below shows the strengths and weaknesses of some laboratory tests available for measuring hemostasis and their applicability in liver disease patients

Some professional societies have recognized the weakness of the INR as a measure of bleeding risk. The American Association for the Study of Liver Diseases (AASLD) practice guideline on liver biopsy mentions that there is no specific PT-INR level that clearly predicts bleeding during or after biopsy. The Society of Interventional Radiology Standards of Practice Document for the management of coagulation status before image-guided interventions recommends that moderately elevated coagulation times should not be assumed to represent increased bleeding risk, but recommends correction with FFP (or vitamin K) to an INR of 2.0 for low-risk procedures and 1.5 for moderate-risk or higher-risk procedures. However, this recommendation does not differentiate between liver disease patients and those who are therapeutically anticoagulated with vitamin K antagonists, and is based on only a Delphi consensus recommendation of a group of interventional radiologists

Variceal bleeding is one of the most common bleeding complications experienced by patients with advanced liver disease at the rate of about 8% per year after the onset of cirrhosis.

Risk factors for bleeding are predominantly related to hemodynamic and mechanical parameters such as hepatic vein-portal pressure gradient, varix size, their appearance (red marks and purple color), and the severity of the underlying liver disease. Limited data to suggest that coagulopathy is directly related to variceal bleeding risk, although increased markers of fibrinolysis were predictive of eventual variceal bleeding. The existence of the platelet plug (nipple sign) as a high-risk marker for variceal bleeding indicates at least some transient role of primary hemostasis in acute bleeding.

There are no specific guideline recommendations on coagulation parameters for prophylactic esophageal variceal band ligation (EVBL). Also, there is no evidence supporting prophylactic transfusion before EVBL in routine practice due to paucity of data. Non-selective beta-blockers alone would be the preferred therapy for primary bleeding prophylaxis in those with coagulation disorders. Other recommendations are mentioned below.

There is a lot of variability across guidelines on recommendations to minimize bleeding during invasive procedures. However, one golden rule would be to delay elective procedures during acute events that might upset the rebalanced hemostatic system in cirrhosis patients such as acute infection, severe acute alcoholic hepatitis, and uremia, and aggressively manage these events prior to the procedure.

Also, the decision to proceed with elective or semi-elective procedures should not only be decided on the INR and platelet counts but also on other factors such as severity of comorbidities of the patient, the necessity of the procedure , accessibility of the procedural site to mechanical hemostasis methods, and the ability to detect early bleeding at the site. Persistent post-operative wound, mucosal or puncture site bleeding could be a sign of hyperfibrinolysis and, hence, surgical teams should be watchful and mange it accordingly. Other specific measures are mentioned below.

PVT is a common event in patients with cirrhosis, with a prevalence of at nearly 11% in patients with well-defined cirrhosis. Growing evidence suggests that treatment or prevention of PVT with low-molecular-weight heparin (LMWH) in selected cirrhosis patients can prevent intrahepatic thrombotic disease and re-cannulate or resorb early clots. Studies show that pre-emptive treatment may lead to significant benefit in the prevention of PVT formation, a lower chance of first hepatic decompensation, and better survival in cirrhotic patients with a high risk for PVT.

In spite of abnormal INR values and thrombocytopenia, multiple studies confirm the risk of peripheral thromboembolic disease such as deep-vein thrombosis (DVT) and pulmonary embolism (PE) in cirrhosis patients. A low protein state (serum albumin less than 2.8 g/dL) is a rough indicator to predict the increased risk for VTE.

Treatment for new diagnoses of VTE should essentially adopt the same protocol as for PVT, except if a delay in treatment is expected, e.g., high-risk esophageal varices eradication where a temporary inferior vena cava filter may be considered.

ALF is an uncommon but profound hepatic synthetic dysfunction characterized by metabolic disarray, highly abnormal INR and typical laboratory markers of coagulation, alterations in immunologic function, and, ultimately, cerebral edema.

A recent study by the U.S. ALF Study Group reported that despite the markedly elevated INR in most patients with ALF, there appears to be a minimal global effect on hemostasis (measured by whole blood clotting) and a general hypofibrinolytic state due to decreased plasminogen and elevated plasminogen activator type 1. Thus, there exists a clinical state of relative hemostasis despite great disturbances in INR.

The management of coagulopathy in liver disease is a quite a challenge for the clinician, with the lack of accurate, reliable and clinically available testing methods to ascertain the true state of hemostasis. Some patients with chronic liver disease may be predisposed to bleeding, some to hypercoagulation, and some may be in a stable balance, thereby demanding a more situation-based clinical approach to each situation