Should practitioners administer these drugs to patients with advanced liver disease, despite the risks?
Historically, patients with liver cirrhosis have been thought to be “auto-anticoagulated,” naturally protected against venous thrombotic disease. This concept has since been debunked and replaced with the understanding that advanced fibrosis promotes anti-coagulant and pro-thrombotic states.
Specifically, liver cirrhosis leads to decreased synthesis of the majority of clotting factors, thereby increasing the risk of bleeding in patients with advanced liver disease. However, patients with fibrosis have decreased levels of anticoagulation factors, such as protein C and antithrombin, which promote a pro-thrombotic state. This seemingly contradictory phenomenon places patients with cirrhosis and healthcare providers in a challenging position: should physicians administer prophylactic anticoagulant drugs to patients with cirrhosis? On the one hand, the risk of bleeding increases with the use of anticoagulant drugs; however, without these drugs, patients could be at risk for developing venous thrombotic disease.
In an article in press for publication in Journal of Hepatology, Mark Thursz, MD, professor of hepatology from Imperial College in London, and colleagues, attempt to address this difficult question.
They introduce the issue of prophylactic anticoagulation by presenting a case study of a man in his late 50s who suffers from chronic hepatitis C with liver cirrhosis. After multiple hospital visits, the patient was admitted to the emergency department complaining of painful swelling in his left leg, which testing later revealed to be a blood clot in his left femoral vein. During previous hospital admissions, physicians opted not to administer prophylactic anticoagulant drugs due to concerns about bleeding. Sadly, the patient suffered a heart attack and died. The cause of death: pulmonary embolism. Dr. Thursz and his colleagues argue that the reasons cited by the physicians against prophylaxis did not make a strong enough case and that the patient could have benefited from anticoagulant drug therapy. They use this case study to pose a series of questions that seek to address the risk of development of thrombosis in patients who suffer from chronic liver disease and whether or not prophylactic anticoagulant drugs should be administered to them.
Before determining if anticoagulant drugs should be administered, it is imperative to assess if there is a real need for such measures in patients with cirrhosis. To examine the correlation between cirrhosis and thrombotic disease, Dr. Thursz and his colleagues cite a Danish study comprising 100,000 patients diagnosed with venous thromboembolism. In this study, patients with liver cirrhosis were shown to be 1.7 times more likely to develop thrombosis compared with the general public. The authors also discussed the risk of developing portal vein thrombosis (PVT), but concluded that in those with chronic liver disease, the magnitude of the risk of developing PVT is unclear.
Although patients with cirrhosis seem to be at a higher risk of developing thrombotic disease, current clinical guidelines do not make any recommendations to physicians for the use of anti-coagulants as a prophylactic measure. Therefore, before any changes to clinical guidelines can be made, prospective studies are needed to examine whether patients with cirrhosis could benefit from prophylaxis, and if so, what an ideal drug regimen would look like. Until such studies are conducted, the benefits and disadvantages for each patient need to be assessed on a case-by-case basis, with the ultimate tough decision falling into the hands of the attending physician.
An additional wrench in the works is the issue of accurately assessing anticoagulation status in patients, a critical parameter to consider before administering anticoagulant drugs. Currently, the international normalized ratio (INR), a prothrombin time test, is utilized, where a high INR indicates slow clotting blood and a lower INR means the patient’s blood is clotting faster than normal. Current clinical guidelines support aiming for an INR of 2.0 or 3.0. However, no studies have been conducted to determine if this is a sound approach to monitoring patients with cirrhosis. Overall, more studies are needed to evaluate optimal dosing regimens, as mentioned previously, and to determine a more effective way to assess anticoagulation status.
To return to the original case study, prophylactic anticoagulation was not administered to the patient due to concerns about the risk of bleeding. It is natural to have such trepidations about the safety of such a measure and to question if anticoagulation therapy can be safely and effectively used in patients with cirrhosis without significantly heightening their risk of bleeding. Dr. Thursz and his colleagues concluded, “With careful screening and management of varices, there does not seem to a significantly increased risk of bleeding, implying that patients may be safely anticoagulated either in the setting of prophylaxis or therapeutic treatment.”
In summation, although evidence suggests that patients with advanced liver disease could stand to benefit from anticoagulation as a prophylactic measure, much research is still needed before clinical guidelines can make this recommendation. In the future, studies are needed to determine the ideal dosing regimens for anticoagulation therapy and an effective and accurate way to assess anticoagulation status.
Feature Image Source: ScienceSource/Pasieka
Samar Mahmoud graduated from Drew University in 2011 with a BA in biochemistry and molecular biology. After two years of working in industry as a quality control technician for a blood bank, she went back to school and graduated from Montclair State University in 2016 with a MS in pharmaceutical biochemistry. She is currently pursuing her PhD in molecular and cellular biology at the University of Massachusetts at Amherst.