Coagulation Homeostasis in Liver Disease

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Abbreviations

FFP

fresh frozen plasma

htn

hypertension

INR

international normalized ratio

PVT

portal vein thrombosis

ROTEM

rotational thromboelastometry

vWF

von Willebrand factor

Key Points

• Where the patients with liver disease were traditionally viewed as being “auto‐anticoagulated,” it has recently been recognized that the coagulopathy of liver disease is complex, with the end result being a fragile but rebalanced hemostatic system with features of both hypocoagulation and hypercoagulation.

• Factors that further affect the rebalanced hemostatic system in patients with cirrhosis include infection, renal failure, changes in platelet function (and perhaps altered factor XIII function), and changes in the fibrinolytic system.

• Expanding the blood volume in an attempt to correct an arbitrary elevation in international normalized ratio (INR) can result in exacerbation of portal pressure, and thus worsening of bleeding.

• Conservative transfusion strategies should be used in the bleeding patients with cirrhosis, with pragmatic recommendations for target platelet counts of 50,000 and fibrinogen levels of 120 to 150 mg/dL.

• The decision to anticoagulate the patient with portal vein thrombosis (PVT) in the setting of cirrhosis must carefully weigh the risks and benefits. Among key factors, the decision to treat depends on the presence or absence of associated symptoms; the extent of thrombus, bleeding, and fall risk; and the patient's transplant status.

• Intrahepatic activation of the hemostatic cascade leading to microthrombi may contribute to the development of end‐stage organ atrophy in a process called parenchymal extinction. Further studies are needed regarding the novel idea that prophylactic anticoagulation can decrease the risk for development of PVT and improve survival among patients with cirrhosis.

Managing the coagulopathy associated with liver disease used to be easy. If the INR was prolonged beyond 1.5 or some other societal or locally set cutpoint, the provider gave some plasma (often two units of fresh frozen plasma [FFP]) plus/minus some platelets and then felt confident that the patient had adequate prophylaxis or treatment of bleeding. As a result of these concepts and practices, patients with liver disease became established as among the best blood bank customers around, particularly for plasma administered prophylactically. ¹ In the same historical vein, anticoagulation should be avoided whenever possible in these patients because they are already “auto‐anticoagulated.” This was a fairly obvious conclusion: who can forget the patients with liver failure in the intensive care unit with blood oozing from gums, puncture wound sites, skin tears, and of course, from above and below via the gut. Now things seem extraordinarily complicated and not as simple as they used to be, and there is even talk of therapeutically anticoagulating stable patients with cirrhosis to prevent organ atrophy (Fig. 1). ²

Fig. 1.

(A) In stable cirrhosis, it has now been established that the hemostatic pathway is mostly rebalanced because of a deficit of the liver‐derived anticoagulant factor protein C, which interacts with endothelial‐derived thrombomodulin to inhibit factor V and factor VIII. (B) The net balance may be hypercoagulable with contributions from elevated factor VIII and vWF, and especially within the portal vein vascular bed, slow flow caused by increased resistance and endothelial injury inherent to the underlying liver disease. These changes constitute Virchow’s triad of hypercoagulability, stasis, and vascular endothelial injury. (C) Other factors favor failure of hemostasis in these patients and result in bleeding. These include most importantly portal hypertension and pressure‐driven rupture of the mesenteric vascular bed. Infection and renal failure also contribute to a bleeding diathesis. The former contributes by causing release of endothelial‐derived “heparinoid” substances, which act like heparin, and renal failure, which contributes both by causing uremic platelet dysfunction and exacerbation of volume expansion with exacerbation of portal pressure. Premature clot dissolution (hyperfibrinolysis) is clinically apparent by diffuse mucosal and puncture wound oozing, as well as delayed postprocedure bleeding. It is best treated by antifibrinolytic agents but remains a clinical diagnosis because laboratory measures have proved to be challenging.

What Happened?

A remarkable convergence of studies in the early and mid‐2000s led to a sea change over the past 20 years in how we conceptually approach the hemostatic mechanisms in these patients. ³ These changes began with the emergence of a new concept of the hemostatic cascade, which was cell based involving exposed collagen and activated platelets, which provided a phospholipid scaffold for procession of the hemostatic cascade. This concept both incorporated and significantly diverged from the old paradigm of the “intrinsic” and “extrinsic” hemostatic pathways (the proteases of the clotting cascade generally require a phospholipid membrane on which to work). ⁴ The coagulopathy of liver disease is complex and involves changes in both liver and vascular endothelial‐derived hemostatic factors. In essence, decreased liver‐derived anticoagulant factors such as protein C and antithrombin, and increased endothelial‐derived procoagulant factors, such as von Willebrand factor (vWF) and factor VIII, combine to produce a relatively hypercoagulable state. ⁵ Superimposed on these changes are key factors such as portal hypertension with an engorged mesenteric venous system, infection that is associated with release of endogenous heparinoids, and renal failure with associated volume issues, changes in platelet function and perhaps altered factor XIII function, and changes in the fibrinolytic system. ⁶ The bottom line of these changes is a fragile but rebalanced hemostatic system with features of both hypocoagulation and hypercoagulation that may contribute to both bleeding and pathological thrombosis.

What is Wrong With the INR Test in the Patient With Liver Disease?

As a measure of hemostasis in cirrhosis, the INR has so many deficiencies as to be discarded in this respect. The “INR” was normalized to various thromboplastins in the assessment of warfarin therapy, where it is likely a valid test. However, those criteria fall apart when applied to patients with liver disease unless normalization to liver disease is performed. ⁷ This has been soundly established and results in significant interlaboratory variation in the INR depending on which reagents were purchased by the clinical laboratory. ⁸ , ⁹ Moreover, it has been shown in vitro and recently in vivo that the addition of therapeutic plasma (10 mL/kg, much higher than “2 units FFP”) does not improve thrombin generation and may in fact diminish thrombin generation probably by replenishing anticoagulant protein C. ¹⁰ , ¹¹ Finally, and perhaps most importantly, expanding the blood volume in response to an arbitrarily defined and physiologically unfounded INR cutoff can result in exacerbation of portal pressure, and thus the clinician may unintentionally exacerbate bleeding through engorgement and pressurization of the mesenteric venous system.

How Should One Approach the Risk for Bleeding in the Patient With Liver Disease?

Although there is a paucity of prospective studies, consensus guidance has emerged regarding alternative strategies for bleeding risk management in patients with cirrhosis in light of the well‐founded deficiencies of prior dogma‐driven strategies discussed earlier. ² , ⁶ In the simplest terms in prophylactic measures, this reduces to pragmatic recommendations to aim for platelet counts of around 50,000 and fibrinogen levels of 120 to 150 mg/dL. These recommendations are supported by studies of bleeding in critically ill patients with cirrhosis. ¹² Increasingly, however, whole blood viscoelastic testing (thromboelastography (TEG), rotational thromboelastometry [ROTEM], and sonorheometry) is being successfully used to support more restrictive approaches to prophylaxis without obvious detriment. ¹³ Other key considerations that may impair hemostasis include infection and renal failure as noted earlier. Our understanding of changes in fibrinogen physiology in cirrhosis (dysfibrinogen) is emerging as to whether these changes enhance or diminish clot stability. ¹⁴ Finally, altered homeostasis in the fibrinolytic system can lead to a state of diffuse mucosal and puncture wound bleeding, and delayed postprocedure bleeding because of premature clot dissolution. ¹⁵ This condition can be effectively treated using antifibrinolytic agents such as aminocaproic acid and tranexamic acid.

What About Hypercoagulation in Liver Disease?

PVT is the most obvious manifestation of the hypercoagulable state in patients with liver disease. This problem is distinct from noncirrhotic PVT and clearly relates to the key elements of Virchow's triad in cirrhosis: hypercoagulability, especially from diminished protein C and increased factor VIII and vWF; endothelial injury from the underlying liver disease; and slow flow (stasis) from increased hepatic resistance and/or portosystemic shunts, especially spontaneous splenorenal shunts, which cause a stagnant flow via a sump effect in the portal vein. ¹⁶ Genetic factors such as factor V Leiden or prothrombin mutation may play a small role in this risk and in decisions regarding treatment, but the latter is really more dependent on symptoms, extent of thrombosis, and especially on transplant status. ¹⁷ In general, anticoagulant therapy has been retrospectively associated with greater rates of portal vein repermeation without increased risk for variceal bleeding presumably because of the portal pressure–lowering effect of a patent portal vein. ¹⁸ However, the risk/benefit of therapy requires careful consideration of potentially associated symptoms and the extent of thrombus, as well as bleeding and fall risk. In addition, two other somewhat opposing conditions should be kept in mind. First, PVT, especially when partial or nonocclusive, often spontaneously opens up through the fibrinolytic system of clot remodeling. Second, among patients awaiting transplant, going into surgery with a PVT adds a significant layer of complexity and can adversely affect transplant outcomes. ¹⁶

What is Parenchymal Extinction?

True “end‐stage” cirrhosis is characterized by organ atrophy, which is usually intractable and requires transplantation to rectify. Intrahepatic small‐vessel thrombosis appears to be a major mechanism of this late‐stage progression in a process called parenchymal extinction. ¹⁹ Remarkably, in a subsequent study aimed at preventing PVT in stable cirrhosis with prophylactic enoxaparin, Villa et al.²⁰ demonstrated decreased PVT but also a significantly decreased rate of decompensation and improved survival. ²⁰ Disappointingly, these provocative results have yet to be validated or refuted by larger investigations, which are needed to investigate the suspected link with intrahepatic small‐vessel thrombosis.

Where Are We Now?

It is now established that the INR is not an adequate measure of bleeding risk, and prolongation of this laboratory test in cirrhosis does not represent “auto‐anticoagulation.” It is a reasonable measure of vitamin K antagonist therapy, but in cirrhosis, prolonged INR can be associated with hypercoagulability as noted earlier. Increasingly, measures of fibrinogen, platelet counts, and more recently whole blood viscoelastic tests (TEG, ROTEM, and sonorheometry) are being used as better indicators of the hemostatic system in cirrhosis. Volume expansion is counterproductive in portal hypertension‐related bleeding and should be minimized to avoid engorging the mesenteric venous system. In contrast, diffuse mucosal or puncture wound bleeding should be recognized as premature clot dissolution (hyperfibrinolysis) due to changes in the plasminogen‐plasmin activator system and are better treated with antifibrinolytic agents. Intrahepatic activation of the hemostatic cascade may underlie the development of end‐stage organ atrophy caused by microthrombi in a process called parenchymal extinction. Further studies are needed to assess the possible benefit of chronic anticoagulation in stable cirrhosis to prevent progression of clinical disease. Regarding PVT, the most overt and common manifestation of the hypercoagulable state in cirrhosis, decisions regarding therapy must be carefully weighed in light of thrombus burden, symptoms, bleeding risk, fall risk, transplant status, and with knowledge that lesser clot burden often resolves without specific intervention.