Journal of Hepatology
Volume 46, Issue 4 , Pages 727-733, April 2007

Abnormalities of hemostasis in chronic liver disease: Reappraisal of their clinical significance and need for clinical and laboratory research

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine and Medical Specialties, University and IRCCS Ospedale Maggiore, Mangiagalli and Regina Elena Foundation, Via Pace 9, 20122-Milano, Italy

published online 05 February 2007.

Article Outline

The derangement of hemostasis in patients with chronic liver disease has long been thought to be causally related to the bleeding events seen in these patients. However, the relatively poor correlation between bleeding and the peripheral indices of hemostasis together with the recent findings of the literature that thrombin generation as well as platelet adhesion are normal in these patients challenge this concept and question the usefulness of conventional tests in assessing the hemorrhagic risk, as well as the appropriateness of therapeutic strategies meant to correct abnormal hemostasis tests. This article reviews the abnormalities of primary hemostasis (interaction between platelets and vessel wall), coagulation (thrombin generation) and fibrinolysis in patients with chronic liver disease and proposes areas needing further clinical and laboratory research.

 

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1. Introduction 

Abnormal hemostasis tests and bleeding are often associated in patients with chronic liver disease. The concept of a causal relationship is widely accepted among clinicians, as demonstrated by the common practice of screening patients with hemostasis tests and of treating those with abnormal values in order to correct the identified abnormalities prior to liver biopsy or other potentially hemorrhagic procedures. Recent findings of the literature challenge this concept and question the usefulness of conventional tests in assessing the hemorrhagic risk, as well as the appropriateness of therapeutic strategies meant to correct abnormal hemostasis tests. In this article we review the situation with respect to the abnormalities of primary hemostasis mechanisms, coagulation and fibrinolysis in patients with chronic liver disease and propose areas needing further clinical and laboratory research.

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2. Primary hemostasis 

Primary hemostasis may be defined as the interaction between platelets and the vessel wall at sites of vascular injury. The chain of events leading to the formation and consolidation of the platelet plug is initiated when circulating platelets adhere to the subendothelium. This is mediated by the exposure on platelet membranes of specific receptors for the plasma adhesive proteins (mainly von Willebrand factor) followed by the adhesion of platelets to the components of the extracellular matrix and the subsequent aggregation to one another. Normal platelet numbers and function as well as normal plasma von Willebrand factor are therefore essential for primary hemostasis. Chronic liver disease is characterized by a variable degree of thrombocytopenia due to increased platelet destruction or to increased splenic and/or hepatic sequestration [1], and by thrombocytopathy due to defective thromboxane A2 synthesis, storage pool deficiency and abnormalities of the platelet glycoprotein Ib [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. These complex defects can be documented through specific tests (i.e., platelet count, aggregometry, cytofluorimetry) or through the measurement of the skin bleeding time, which has long been regarded as the global test for primary hemostasis. Evidence stemming from clinical practice and from the literature shows that the bleeding time is prolonged in up to 40% of patients with cirrhosis [12]. However, it is not firmly established whether or not this prolongation is of clinical relevance. Boberg and associates showed that a prolonged bleeding time (more than 12min) was associated with a fivefold increased risk of hemoglobin reduction after liver biopsy, but the association with other clinical manifestations of bleeding was not evaluated [13]. However, three different studies performed over the years showed that desmopressin (a synthetic analogue of vasopressin) when given intravenously [14], [15] or subcutaneously [16] shortens the prolonged bleeding time in patients with cirrhosis, thus supporting the views that the bleeding time may play a role. On the other hand, it should be emphasized that studies evaluating clinical end points after desmopressin infusion and bleeding time shortening gave negative results. For instance, de Franchis et al. showed that desmopressin does not improve the efficacy of terlipressin in controlling acute variceal bleeding in cirrhotics [17], and Wong and associates showed that desmopressin does not decrease blood loss and transfusion requirements in patients undergoing hepatectomy [18]. More recently, Lisman and associates using a test system carried out under flow conditions that mimics closely what occurs in vivo showed that the high levels of von Willebrand factor typically found in cirrhosis support normal platelet adhesion in these patients, thus compensating for the defects of platelet numbers and function [19]. All these findings taken together support the hypothesis that the prolongation of the bleeding time in this setting is probably due to causes other than moderate thrombocytopenia or thrombocytopathy and cast doubt about the value of the bleeding time in predicting the risk of bleeding. Accordingly the bleeding time, which is still ordered for patients with cirrhosis before liver biopsy in about half of the centers surveyed in a recent investigation [20], should be discontinued. To ascertain whether defects of primary hemostasis are truly (and to what extent) related to bleeding in cirrhosis, laboratory tests should go beyond the bleeding time. Methods carried out under flow conditions such as that used by Lisman and associates [19] are potential candidates, but they are too complex to be put in practice and validated in clinical trials. The platelet functional analyzer (PFA-100) has been advocated as a simple substitute for the bleeding time, but it has not yet been evaluated for its clinical usefulness in predicting the risk of bleeding in patients with liver cirrhosis.

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3. Coagulation 

Coagulation is defined as the chain of events which, through the activation of plasmatic coagulation proteins, leads to thrombin generation. Thrombin in turn converts fibrinogen into fibrin which is eventually stabilized by activated factor XIII. This is a highly integrated cellular and humoral process, which is initiated when plasmatic activated factor VII (factor VIIa) comes into contact with its specific cell receptor tissue factor (TF) exposed on cellular surfaces at sites of vascular injury. The complex factor VIIa-TF is then able to activate factor X, which in turn catalyzes the (factor Va-mediated) generation of thrombin from factor II (prothrombin). The complex factor VIIa-TF is also able to activate factor IX, which interacts with activated factor VIII on activated platelets bound to the extracellular matrix. This complex generates additional amounts of activated factor X, thus magnifying the process of thrombin generation. In normal conditions thrombin generation is tightly controlled by the anticoagulant system, which includes antithrombin, proteins C and S and the tissue factor pathway inhibitor (TFPI). The balance between the pro- and anti-coagulant factors prevents unwanted thrombin generation and fibrin deposition, whereas its disruption results in hypo- or hyper-coagulability.

3.1. Hypocoagulability 

It is well known that cirrhosis is characterized by an impaired synthesis of all coagulation factors (except factor VIII) [21] and that this complex defect can be documented through the measurement of individual coagulation factors, or through the prolongation of such global tests as the old and time-honored prothrombin time (PT) and the activated partial thromboplastin time (APTT), which are cumulatively responsive to most coagulation factors synthesized by the liver. On the other hand, it is known that PT and APTT do correlate poorly with bleeding after liver biopsy or other potentially hemorrhagic procedures in patients with cirrhosis [22], [23], [24], [25], [26], [27], [28]. One may wonder why. PT and APTT are inadequate to reflect the balance of coagulation as it occurs in vivo, especially in cirrhosis, a condition where the naturally-occurring anticoagulants protein C, antithrombin and TFPI are reduced in parallel with pro-coagulant factors. Furthermore, protein C needs to be activated in order to exert its anticoagulant activity. In vivo protein C activation is mediated by thrombin and the rate is enhanced manyfold by the endothelial receptor thrombomodulin [29]. Also antithrombin needs to be activated and this is accomplished by such glycosaminoglycans as heparan sulphate and others, which are located on endothelial cells [30]. It should be appreciated that neither the plasma nor the reagents needed to perform PT and APTT do contain thrombomodulin or glycosaminoglycans. Therefore, PT and APTT are responsive only to the thrombin generated as a function of the pro-coagulant factors, but not to the inhibition of thrombin mediated by anticoagulant factors. Accordingly, the PT and the APTT are suitable tests to investigate congenital deficiency of pro-coagulant factors, but they are unfit to investigate congenital deficiencies of anticoagulants or acquired deficiencies of both the pro- and the anti-coagulant factors as they occur in liver cirrhosis. Recently, this hypothesis was tested by investigating the balance of coagulation in patients with liver cirrhosis and healthy subjects by measuring pro- and anti-coagulant factors by means of conventional tests as well as the endogenous thrombin potential (ETP) [31]. The latter was measured under in vitro conditions which mimic more closely what occurs in vivo. Briefly, platelet-free plasma was incubated with small amounts of TF as coagulation trigger and exogenous phospholipids as platelet substitutes. The test was performed in the absence or presence of soluble thrombomodulin as protein C activator. The amount of thrombin generated over time was monitored by means of a synthetic fluorogenic substrate and the parameters of the thrombogram (see Fig. 1) were calculated by a dedicated software according to Hemker et al. [32] as detailed by Chantarangkul et al. [33]. The area under the thrombin generation curve is defined as the ETP expressed as fluorogenic units (FU min) or thrombin concentration (nM min) and represents the balance between the action of pro- and anti-coagulant factors in plasma. This method was used to investigate plasmas from patients with liver cirrhosis and healthy subjects comparable to the patient population for age and sex [31]. As expected the patients with cirrhosis had prolonged PT and APTT and decreased levels of protein C, antithrombin and factor II [31]. When the ETP was measured in the absence of thrombomodulin, patients showed significantly lower levels than control subjects (308FU min versus 451FU min, p<0.001) [31]. This was not unexpected as it did reflect the partial defect of pro-coagulant factors not balanced by the parallel defect of the anticoagulants, especially protein C that is in only partially activated in the absence of thrombomodulin. When the test was performed by adding soluble thrombomodulin the control population generated less thrombin, but the difference between patients and control subjects was no longer statistically significant (209FU min versus 188FU min, p=0.50) [31]. The conclusion stemming from this study is that coagulation is normal in cirrhotics when assessed with global tests reflecting the function of pro- and anti-coagulant factors. This finding questions the usefulness of traditional coagulation tests in assessing the hemorrhagic risk in cirrhotics and probably in other conditions where both the pro- and the anti-coagulant pathways are impaired. However, the translational application of this finding warrants clinical evaluation. One of the limitations of the previous study was that ETP was measured in platelet-free plasma. Under the aforementioned assay conditions, thrombin is generated solely as a function of pro- and anti-coagulant factors and does not account for platelets which are known to contribute significantly through their pro-coagulant activity mediated by the exposure of membrane phospholipids [34]. A recent study investigated such an effect by measuring ETP under the same assay conditions, but in platelet-rich plasma [35]. In these experiments exogenous phospholipids were omitted from the assay and the numbers of platelets from patients and control subjects were adjusted by appropriate dilutions of the autologous platelet-free plasma into autologous platelet-rich plasma to a standard count of 100×109/L or to the original platelet count in whole blood for each patient and control subject [35]. When the ETP was measured in the absence of thrombomodulin in plasma with platelet numbers adjusted to a standard count, patients generated significantly less thrombin than control subjects (Fig. 2), but (as for platelet-free plasma) when the ETP was measured in the presence of thrombomodulin the differences were abolished (Fig. 2).

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  • Fig. 1. 

    Typical thrombin generation curve (thrombogram) obtained in plasma after activation of coagulation by small amounts of tissue factor and exogenous phospholipids or platelets (see text for more details). The area under the curve is defined as the endogenous thrombin potential (ETP).

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  • Fig. 2. 

    ETP expressed as thrombin concentration times minutes for control subjects (closed circles) and cirrhotics (open circles) in the presence or absence of soluble thrombomodulin in platelet-rich plasma. Platelet numbers were adjusted to 100×109/L. Horizontal bars represent median values. N.S., not significant at the 0.05 level. Reprinted with the permission of the publisher from A. Tripodi et al., Hepatology 2006;44:440–445.

Conversely, when the ETP was measured in plasma with platelet numbers adjusted to the original whole blood count, thrombin generation was significantly lower in patients than in control subjects irrespective of the addition of thrombomodulin (Fig. 3). Notably, patients with the lowest platelets count were those who generated the least amounts of thrombin. In summary, these experiments confirm the role played by platelets in thrombin generation and indicate that platelets from cirrhotics are qualitatively able to support normal thrombin generation provided that they are in sufficient number. Analyses of the correlation between ETP and platelet numbers allow to estimate the number of platelets needed to secure near-normal thrombin generation. This value corresponds to 56×109/L which is close to the threshold value used in common practice for liver biopsy or intracranial pressure monitor placement [36].

  • View full-size image.
  • Fig. 3. 

    ETP expressed as thrombin concentration times minutes for control subjects (closed circles) and cirrhotics (open circles) in the presence or absence of soluble thrombomodulin in platelet-rich plasma. Platelet numbers were adjusted to the individual patient or control subject whole blood counts. Horizontal bars represent median values. Reprinted with the permission of the publisher from A. Tripodi et al., Hepatology 2006;44:440–445.

The above information on thrombin generation in platelet-free and platelet-rich plasma is consistent with the concept that coagulation is not abnormal in liver cirrhosis in spite of the fact that traditional coagulation tests are often abnormal. These findings point at two important considerations. First, they question the usefulness of such pro-coagulant agents as recombinant factor VIIa in controlling bleeding and explain their relatively poor clinical efficacy observed in the whole trial populations of recent studies in spite of the fact that normalization of the prolonged PT was achieved for the majority of treated patients [37], [38], [39], [40]. Second, they challenge the commonly used practice of correcting the PT as the main target to assess the efficacy of pro-coagulant agents. Patients should be stratified by using more appropriate tests.

3.2. Hypercoagulability 

The balance of coagulation afforded by the concomitant reduction of the pro- and anti-coagulant proteins may explain why patients with chronic liver disease are not protected from thrombotic events which are observed despite the concomitant prolongation of conventional coagulation tests. This apparent paradox may be explained if one considers that patients with liver disease may generate normal or even higher than normal thrombin and may occasionally be exposed to acquired or genetic risk factors leading to thrombosis. Portal vein thrombosis is not an infrequent event [41], especially in cirrhotics who are carriers of such prothrombotic gain-of-function mutations as factor V Leiden or the prothrombin G20210A [42]. The presence of these mutations might also be exacerbated by the elevated levels of factor VIII, which are typically found in patients with cirrhosis [43]. In this respect the concept of considering the coagulopathy solely on the basis of the prolonged traditional coagulation tests does not hold true and should be reconsidered.

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4. Fibrinolysis 

The fibrinolytic system is a highly integrated system which operates whenever fibrin deposition does occur. It includes a pro-enzyme (plasminogen) which can be converted into the active enzyme (plasmin), which in turn degrades fibrin into various degradation products. The conversion is tightly regulated by a series of activators, such as the tissue plasminogen activator (tPA) and the urokinase plasminogen activator (uPA), and anti-activators such as the specific inhibitors of tPA (mainly PAI-1) and plasmin inhibitors (mainly alpha1-plasmin inhibitor). Recently a new inhibitor, named thrombin activatable fibrinolysis inhibitor (TAFI), has been described. It is a pro-carboxypeptidase synthesized by the liver, which upon activation by thrombin or plasmin, mediates the removal of the lysine residues from fibrin, thus preventing the binding and activation of plasminogen which do occur on its surface. The balance of fibrinolysis is important to prevent unwanted plasmin generation and the perturbation of this balance may cause either hyper- or hypo-fibrinolysis. The occurrence of hyperfibrinolysis in patients with cirrhosis has been advocated but is still debated [36]. The reasons for this uncertainty, as for primary hemostasis and coagulation, probably rest on the lack of appropriate laboratory tests for its evaluation. Most observations are restricted to the measurement of individual components rather than to the evaluation of the overall activity which would take into account the balance of pro- and anti-fibrinolytic factors. For instance, cirrhosis has been found to be associated with decreased levels of plasminogen, alpha1-plasmin inhibitor, factor XIII or TAFI, but also with increased levels of tPA or its inhibitor PAI-1 [44], [45], [46], [47], [48], [49]. Special attention has been focused on TAFI, postulating that the decreased levels of this inhibitor might explain the condition of hyperfibrinolysis in cirrhosis. Recently, Lisman et al. [50] tested this hypothesis by measuring the individual components of fibrinolysis as well as employing a global test to assess the overall plasmatic fibrinolytic capacity and concluded that the deficiency of TAFI in cirrhotics is not associated with increased plasma fibrinolysis, suggesting (as for coagulation) that the balance of fibrinolysis is restored by the concomitant reduction of both pro- and anti-fibrinolytic factors [50]. Opposite results and conclusions were reported by Colucci et al. [51]. This controversy has not yet been resolved and is probably explained by the different design of the global fibrinolysis assays employed in the two studies, leaving room for further investigation in order to clarify the role of fibrinolysis in this setting. To this end the measurements of the individual components of the fibrinolytic pathway are unlikely to help and probably lead to an overestimation of the importance of hyperfibrinolysis in cirrhosis. Future efforts should be directed to develop simple global tests which should then be evaluated in clinical studies to assess the extent of fibrinolysis derangement in cirrhosis.

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5. Conclusions and future directions 

The derangement of hemostasis in patients with chronic liver disease has long been thought to be causally related to the bleeding events seen in these patients. However, the relatively poor correlation between bleeding and the peripheral indices of coagulation and primary hemostasis challenged this concept to such an extent that in a recent informal poll [36] relatively few respondents perceived the PT as a good predictor of bleeding in patients undergoing potentially hemorrhagic procedures. This is in keeping with the recent observation that thrombin generation in vitro is normal when assessed by means of a global test reflecting the interaction of pro- and anti-coagulant factors. Yet, when conventional coagulation tests are prolonged, it is still relatively common practice to implement prophylactic measures based upon the use of fresh frozen plasma or other hemostatic agents in patients who are about to undergo liver biopsy or other potentially hemorrhagic procedures. This counterintuitive behavior may be explained by the lack of sound evidence based on clinical trials and is probably driven by legal considerations. Clinical studies addressing the value of old and newer tests of primary hemostasis and coagulation are urgently needed. These studies should include patients with mild-to-moderate laboratory abnormalities awaiting potentially hemorrhagic procedures. Patients should be randomly assigned to either prophylactic or no therapy and then assessed for objectively documented bleeding. Until data coming from these studies become available, the best approach rests on clinical judgment based on prior bleeding and on the awareness that any prophylactic procedure may expose the patient to unnecessary risks such as those of transfusion-transmitted infections, exacerbation of portal hypertension or transfusion related acute lung injury (TRALI) as they may occur after infusion of large volumes of fresh frozen plasma. Another possibility which waits to be investigated in clinical trials is platelet transfusion or treatment with thrombopoietin [52]. Transfused platelets would provide a suitable phospholipid surface to complement the normal thrombin generation provided by plasma, thus securing normal coagulation even in those patients with severe thrombocytopenia [35].

In conclusion, the present evidence suggests that the hemostatic derangement in patients with chronic liver disease is related to their bleeding problems much less than previously thought. Other culprits should be investigated, such as the hemodynamic alterations secondary to portal hypertension, endothelial dysfunctions, bacterial infections and renal failure. Adequate interventions aimed at correcting the above conditions should be actively pursued in patients with chronic liver disease in order to treat or prevent clinical bleeding.

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PII: S0168-8278(07)00056-6

doi:10.1016/j.jhep.2007.01.015

Journal of Hepatology
Volume 46, Issue 4 , Pages 727-733, April 2007

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