Chronic Liver Disease and Hemostasis

Author: Jennifer Robertson, MD, MSEd // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW Medical Center / Parkland Memorial Hospital)

Case

A 57-year-old male with a history of asthma, type 2 diabetes and end stage liver disease due to hepatitis C and alcohol abuse presents to the emergency department with a chief complaint of right lower extremity pain, edema and erythema. He denies trauma, fevers or any personal history of blood clots. His home medications include an albuterol inhaler and metformin 500mg twice daily.

Initial vital signs are unremarkable except for mildly low blood pressure of 90/60 mmHg which he states is his baseline blood pressure. His right lower extremity has the following appearance:

Initial laboratory tests that were ordered in triage show a hemoglobin of 10.2g/dL, a normal white blood cell count, a platelet count of 60 x 103/uL, a normal basic metabolic panel except for a creatinine of 1.5 mg/dL and an international normalized ratio (INR) of 1.7.

A Doppler ultrasound was also ordered in triage as the physician assistant in triage was worried about a blood clot. However, the ultrasound technician has not arrived to the emergency department yet. You consider discontinuing this ultrasound because this most certainly could not be a blood clot with such a low platelet count and elevated INR? Or could it be?

Hemostasis and the Liver

The balance between bleeding and clotting is complicated. It involves platelets, clotting factors, anti-coagulant factors and anti-fibrinolytic factors (1). The first step in coagulation is vasoconstriction after injury. However, the next two steps, (a) formation of platelet plug and (b) the coagulation cascade and the formation of thrombin, are important steps that the liver helps coordinate.

Formation of a platelet plug obviously requires platelets. However, most patients with cirrhosis have thrombocytopenia. It is thought that the majority of thrombocytopenia is due to splenic sequestration, however, it is also thought to be due to decreased production of thrombopoietin in the liver (2). Thrombopoietin (TPO) is a hormone that is mostly produced in the liver and it regulates the production of platelets. Patients with liver disease are known to have reduced levels of TPO and thus, thrombocytopenia is thought to be partially due to lower levels of this hormone (2)

Another important aspect of the concept of hemostasis is the clotting cascade. This is the last step of hemostasis where the platelet plug is reinforced with a fibrin mesh. While the key steps of coagulation cascade are complicated and difficult to remember, it is important to broadly understand and review. Below is a diagram demonstrating the coagulation cascade.

The liver not only produces the majority of the coagulation factors, anticoagulant proteins and elements of the fibrinolytic system, but it also helps clear these factors from the bloodstream (1). The clotting factors include all of the vitamin K dependent proteins (Factors II,VII, IX, X, protein C, protein S and protein Z) and factors V, XIII, fibrinogen, antithrombin and plasminogen. There are other factors such as von Willebrand factor and thrombomodulin that are synthesized elsewhere but it is important to know the importance the liver has in the process of hemostasis. In addition, it should be remembered that protein C, protein S and anti-thrombin are important anti-coagulants that inactivate the various clotting factors (1).

Finally, fibrinolysis is also an important part of hemostasis, except that it helps break up clots, rather than form them. Proteins in the fibrinolytic system are also produced by the liver.  In liver disease, tissue plasminogen activator is increased along with lower levels of alpha 2 antiplasmin and thrombin activator fibrinolysis inhibitor. However, there are also increased levels of plasminogen activator inhibitor, which balances out the increased fibrinolytic activity (3).

Given the large number of components of hemostasis that are produced by the liver, it is not surprising that patients with cirrhosis are considered to have abnormal hemostasis. However, the pathophysiology is complicated and patients with cirrhosis may actually be prone to clotting just as much as bleeding (3). In fact, patients with cirrhosis may even be slightly more at risk for clotting than those without liver disease (4).

Bleeding and Clotting in Cirrhosis

Patients with chronic liver disease often have low platelet counts, elevated international normalized ratios (INR) and abnormal activated partial thromboplastic times (aPTT). (5). While these tests may be abnormal in patients with cirrhosis, this does not mean that these patients are naturally anticoagulated and can never develop blood clots (6, 7). In addition, these tests do not necessarily predict bleeding events, especially during procedures (3, 5, 8).

As previously mentioned, hemostasis starts with vasoconstriction but platelet plugs are formed next.  This platelet plug step is primarily mediated by platelets and plasma von Willebrand factor (vWF) (5). As a review, vWF is a large protein involved in platelet adherence. After a vessel wall is damaged, vWF finds the damage and binds to exposed collagen fibers in the subendothelium. After this, the vWF -collagen complex binds to platelet glycoproteins and eventually a platelet plug is formed (9).  While patients with cirrhosis have thrombocytopenia, they also have been found to have higher levels of vWF and also decreased levels of the vWF cleaving protease, ADAMTS13, and adequate platelet adhesion (9, 10, 11).  Because of these factors, platelet adherence may be normal or near normal in patients with cirrhosis, despite lower absolute platelet levels (9, 23).

The coagulation cascade is the last step of hemostasis and this step essentially reinforces the platelet plug with a fibrin mesh. As seen in the above diagram, the cascade involves several coagulation factors and thrombin and fibrin. The coagulation tests of PT and aPTT measure the overall speeds of how blood clots via the intrinsic and extrinsic pathways. The aPTT measures the intrinsic and common coagulation pathways while the PT measure the speed of clotting via the extrinsic pathway. In patients with cirrhosis, these tests are usually abnormal because of the abnormal levels of clotting factors (produced by the liver) in the body (13). However, just as with platelet counts, the abnormal coagulation tests do not necessarily predict bleeding or clotting in patients with liver disease (5).  Standard coagulation tests including the PT and aPTT were developed to monitor therapy and also evaluate for single factor deficiencies such as hemophilia. They were not developed to evaluate in-vivo hemostasis and overall have not been found to correlate well with bleeding risk (8, 12).

Studies have demonstrated that in patients with cirrhosis, the hemostatic system manages to balance itself out because decreased procoagulant proteins are accompanied by decreased levels of anti-coagulant proteins (1, 3, 14). In addition, the standard laboratory tests of the PT and aPTT are not very sensitive to detect levels of anticoagulation proteins, nor can they detect overall thrombin formation (3, 5, 12). The standard PT and aPTT were designed to measure only the early phases of thrombin and initial clot formation. However, in patients with liver disease, this first step is slower due to the lower levels of plasma coagulation factors. Thus, the standard PT and aPTT are erroneously prolonged in these patients (3, 12).  In fact, there is also evidence to show that patients with cirrhosis actually have intact thrombin generating capacity (10, 15, 16). This may, in part, be due to the fact that patients with liver disease are resistant to the action of thrombomodulin, which is the main activator of protein C (15, 16).

Given the limitations of the standard PT/aPTT, other testing modalities including whole blood global viscoelastic tests, have been examined to better evaluate clotting in patients with liver disease. One of these tests, rotational thromboelastometry (ROTEM), may help provide more accurate and useful information regarding the hemostatic state in patients with liver disease (12). Viscoelastic tests are helpful because, unlike the standard coagulation tests, they continuously evaluate rates of coagulation from initial clot formation to final clot strength (12).  They also provide a better idea of a patient’s blood status in vivo and provide information on the presence and severity of fibrinolysis and coagulability (12, 16). While viscoelastic tests are not widely used, they have recently been studied in patients with cirrhosis and found to paint a better overall picture of these patient’s clotting and bleeding tendencies (16, 17, 18, 19).

What about fibrinolysis? It has been demonstrated that patients with cirrhosis also have reduced levels of fibrinolysis inhibitors and thus, must have an overall increase in fibrinolysis. There have been varying reports on this, with some studies showing increased fibrinolysis in patients with cirrhosis (20, 21), while others showing a more “balanced” fibrinolytic state. In other words, some reports show overall increased fibrinolysis while others show decreased levels of fibrinolytic inhibitors and decreased levels of the fibrinolytic factors and thus, no significant difference in the rates of fibrinolysis in patients with cirrhosis (3, 22, 23).

Because of these variations in findings, further studies are needed. However, at least currently, the literature supports normal or even enhanced clotting tendencies in patients with cirrhosis, despite possibly increased fibrinolytic states (4, 6, 7, 9, 19, 20, 21).  The take home point is not the nuances of testing but rather, that patients with cirrhosis can clot and will clot, even with thrombocytopenia and elevated PT/INR levels.

 Conclusions

While more studies need to be conducted on bleeding and clotting risk in patients with cirrhosis, especially with newer, more sensitive tests for the coagulation system, the point of this review is that patients with cirrhosis CAN form clots. Thus, if there are any signs and/or symptoms of a blood clot in your next patient with cirrhosis, then adequate workup should be obtained.

References/Further Reading

1. DeSancho M, Pastores S. The liver and coagulation. Textbook of Hepatology: From Basic Science to Clinical Practice 2007; 3:255-3.
2. Hayashi H, Beppu T, Shirabe K, Maehara Y, Baba H. Management of thrombocytopenia due to liver cirrhosis. World J Gastroenterol. 2014; 20(10):2595-605.
3. Mannucci PM. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No. J Thromb Haemost 2006; 4: 721–3.
4. Søgaard KK, Horváth-Puhó E, Grønbæk H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case–control study. Am J Gastroenterol. 2009; 104(1):96-101.
5. Tripodi A, Mannucci PM. Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research. J Hepatol. 2007; 46(4):727-33.
6. Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. CHEST 2010; 137(5):1145-9.
7. Schaden E, Saner FH, Goerlinger K. Coagulation pattern in critical liver dysfunction. Curr Opin CritCare 2013; 19(2):142-8.
8. Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence‐based review. Transfusion 2005; 45(9):1413-25.
9. Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, Leebeek FW. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44(1):53-61.
10. Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41(3):553-8.
11. Beer JH, Clerici N, Baillod P, Von Felten A, Schlappritzi E, Büchi L. Quantitative and qualitative analysis of platelet GPIb and von Willebrand factor in liver cirrhosis. Thrombosis and haemostasis. 1995; 73(4):601-9.
12. Mallett SV, Chowdary P, Burroughs AK. Clinical utility of viscoelastic tests of coagulation in patients with liver disease. Liver Int 2013; 33(7):961-74.
13. Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT, Tripodi A, Trotter JF, Valla DC, Porte RJ, Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 2010; 53(2):362-71.
14. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood. 2010; 116(6):878-85.
15. Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52(3):355-61.
16. Tripodi A, Primignani M, Chantarangkul V, Viscardi Y, Dell’Era A, Fabris FM, Mannucci PM. The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters. Thromb res 2009; 124(1):132-6.
17. Popescu M, Bădărău IA, Bacalbașa N, Tomescu D. To clot or not to clot? A comparison between standard coagulation tests and rotational thromboelastometry in patients with End-Stage Liver Disease.
18. Ben-Ari Z, Panagou M, Patch D, Bates S, Osman E, Pasi J, Burroughs A. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol 1997; 26(3):554-9.
19. Kleinegris MC, Bos MH, Roest M, Henskens Y, Cate‐Hoek A, Van Deursen C, Spronk HM, Reitsma PH, De Groot PG, Cate H, Koek G. Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity. J Thromb Haemost. 2014; 12(10):1647-57.
20. Rijken DC, Kock EL, Guimarães AH, Talens S, Murad SD, Janssen HL, LEEBEEK F. Evidence for an enhanced fibrinolytic capacity in cirrhosis as measured with two different global fibrinolysis tests. J Thromb Haemost 2012; 10(10):2116-22.
21. Colucci M, Binetti BM, Branca MG, Clerici C, Morelli A, Semeraro N, Gresele P. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003; 38(1):230-7.
22. Lisman T, Leebeek FW, Mosnier LO, Bouma BN, Meijers JC, Janssen HL, Nieuwenhuis HK, De Groot PG. Thrombin-fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology. 2001 Jul 31;121(1):131-9.
23. Lisman T, Leebeek FW, Mosnier LO, Bouma BN, Meijers JC, Janssen HL, Nieuwenhuis HK, De Groot PG. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology. 2001 Jul 31;121(1):131-9.