Haemostasis is a multifaceted physiological process which is designed to stop­ bleeding at the site of an injured blood vessel. The coagula­tion cascade works with the combining effects of two processes - one controlling blood clot formation and the other in initiating the anticoagulation system that controls the extension of the clot in order to avoid damage to the organs.

The liver is vital in the construction of haemostasis. It synthesises the majority of the pro- and anticoag­ulant factors and also plays a role in their regulation (for example, clearing clotting factors from circulation through its reticulo-en­dothelial system).

Liver disease significantly affects the coagulation cascade. With the exception of von Willebrand factor, which is secreted by endothelial cells, and calcium, it produces all factors involved in the coagulation process. The production of these factors is impaired when there is hepatic insufficiency.

Individuals with cirrhosis have a reduction in anticoagulant proteins (antithrombin III, protein S, or C), and have an increase of procoagulant factors (factor VIII or von Willebrand factor). Their coagulative condition is classed as a new balance of pro- and anticoagulation fac­tors, described as “rebalanced haemostasis”. This has a disposition to­ward bleeding or thrombotic events depending on the clinical set­tings. The haemostatic balance is much harder to maintain.

Serum albumin and liver cirrhosis

Patients with advanced cirrhosis are highly likely to have hypoalbuminemia caused both by decreased synthesis by the hepatocytes (liver cells) and water and sodium retention that dilutes the content of albumin in the extracellular space. Other factors likely contribute to the development of hypoalbuminemia.

Hypoalbuminaemia and VTE

Albumin is the most abundant circulating protein found in blood plasma. It is synthesised in the liver, however very small amounts are stored in the liver, and is excreted quite quickly into the bloodstream. Its functions include regulating plasma oncotic pressure (pressure applied by plasma proteins on the capillary wall), prevents fluid from leaking into the bloodstream, and is involved in transporting vitamins, enzymes, hormones and other substances around the body.

Hypoalbuminaemia is one of the most prevalent disorders in hospitalised and critically ill patients, and results from a decrease in albumin levels. It is rare for the condition to be caused by a reduction in albumin production; it commonly begins with the insufficient synthesis of albumin due to significant systemic illness.

Causes

• Chronic and advanced hepatic cirrhosis.
• Nutrient deficiency – decreased supply of amino acids to the liver as well as other nutritional deficiencies, mainly iron and zinc.
• Renal loss – nephrotic syndrome and chronic kidney disease.
• Gastrointestinal loss – protein-losing enteropathy is characterised by significant loss of proteins, including albumin, through the gastrointestinal tract.
• Sepsis – is associated with increased vascular permeability and capillary leakage resulting in loss of albumin from the intravascular compartment.

Venous thromboembolism (VTE)

Albumin also includes anticoagulant properties via a heparin-like activity and inhibition of clotting factor biosynthesis by liver cells such as factor VIII and V and platelet aggregation inhibition. A meta-analysis published in June 2024 found that both medical and surgical patients in the study were at a higher risk of VTE, myocardial infarction and stroke compared to individuals without hypoalbuminaemia.

It is hypothesised that the elevated coagulability comes from the imbalance between the loss of anticoagulants (antithrombin III) via the renal system, with increased synthesis of liver procoagulants fibrinogen, factor V and factor VIII); increased platelet activation, decreased fibrinolytic activity, and localised clotting activation in the kidney.

Nephrotic syndrome (NS) is also associated with increased arterial and venous thromboembolism. A 2023 review article found that the risk of arterial thromboembolism was 8-times higher among individuals with NS compared to the general population.

Anticoagulants – hypoalbuminemia has been shown to inhibit the efficacy of antithrombotic treatments and some anticoagulants have a decreased capacity in treating and preventing VTE.

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References

• Bernardi, M., Maggioli, C., & Zaccherini, G. (2012). Human albumin in the management of complications of liver cirrhosis. Critical Care (London, England), 16(2), 211–211. https://doi.org/10.1186/cc11218
• Gounden, V., Vashisht, R., & Jialal, I. (2023, August 28). Hypoalbuminemia. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK526080/
• Di Castelnuovo, A., Bonaccio, M., Costanzo, S., De Curtis, A., Magnacca, S., Persichillo, M., Panzera, T., Bracone, F., Pignatelli, P., Carnevale, R., Cerletti, C., Donati, M. B., de Gaetano, G., Iacoviello, L., Violi, F., Iacoviello, L., de Gaetano, G., Donati, M. B., Cerletti, C., … Morelli, M. (2024). The association between hypoalbuminemia and risk of death due to cancer and vascular disease in individuals aged 65 years and older: findings from the prospective Moli-sani cohort study. EClinicalMedicine, 72, 102627-. https://doi.org/10.1016/j.eclinm.2024.102627
• Leonardi, F., Maria, N. D., & Villa, E. (2017). Anticoagulation in cirrhosis: a new paradigm? Clinical and Molecular Hepatology, 23(1), 13–21. https://doi.org/10.3350/cmh.2016.0110
• Parker, K., Ragy, O., Hamilton, P., Thachil, J., & Kanigicherla, D. (2023). Thromboembolism in nephrotic syndrome: controversies and uncertainties. Research and Practice in Thrombosis and Haemostasis, 7(6), 102162–102162. https://doi.org/10.1016/j.rpth.2023.102162
• Valeriani, E., Cangemi, R., Carnevale, R., Romiti, G. F., Pannunzio, A., Pignatelli, P., & Violi, F. (2024). Hypoalbuminemia as predictor of thrombotic events in patients with community-acquired pneumonia. International Journal of Cardiology, 404, 131942–131942. https://doi.org/10.1016/j.ijcard.2024.131942
• Valeriani, E., Pannunzio, A., Palumbo, I. M., Bartimoccia, S., Cammisotto, V., Castellani, V., Porfidia, A., Pignatelli, P., & Violi, F. (2024). Risk of venous thromboembolism and arterial events in patients with hypoalbuminemia: a comprehensive meta-analysis of more than 2 million patients. Journal of Thrombosis and Haemostasis, 22(10), 2823–2833. https://doi.org/10.1016/j.jtha.2024.06.018