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Hemostasis in chronic liver disease

Patients with advanced cirrhosis have a complex hemostatic disturbance. This event has been always considered to have a relevant role in bleeding, one of the major complication in these patients [1,2], but this established dogma has been challenged in a recent debate [3,4]. Tripodi et al. [5] have recently shown that when blood coagulability is globally measured using a thrombin generation assay, modified by the addition of thrombomodulin and hence becoming sensitive not only to the plasma levels of coagulation factors but also to the reduced levels of naturally occurring inhibitors, patients with cirrhosis form thrombin in amount similar to that of healthy individuals. Moreover, accelerated fibrinolysis, considered an additional contributing event to the bleeding tendency in these patients, was not different between cirrhotic patients and healthy controls in a recent study where this system was explored using a global test sensitive to both activators and inhibitors [6]. Is the role of thrombocytopenia and thrombocytopathy in the bleeding tendency of cirrhotic patients the next dogma to undergo dispute? Thrombocytopenia is a relatively common feature of cirrhotic patients [1,2]. The pathogenesis of this phenomenon is complex, with splenic pooling, increased platelet destruction and impaired platelet production variably contributing as etiologic factors [1,2]. Impaired platelet production is due, at least in part, to the low levels of thrombopoietin [7]. Abnormalities in platelet function are reflected by prolonged bleeding time, impaired aggregation, reduced adhesiveness and abnormal ultrastructure [2], and these functional and morphological abnormalities have been ascribed to an intrinsic platelet defect. More specifically, the platelet defect was related to an impaired transmembrane signalling mechanism [8], together with altered thromboxane A2 production, altered cholesterol content of the platelet membrane and an acquired platelet storage pool defect [8–11]. In our previous studies we have also shown increased AMP and GMP platelet content in cirrhotic patients with defective aggregation [12]. These data may support the hypothesis that increased endothelial synthesis of nitrous oxide (NO) and prostacyclin may reduce platelet response in vivo [12]. Despite the fact that the clinical relevance of thrombocytopathy and thrombocytopenia, together with that of coagulation tests, appears limited in prediction of bleeding, in our opinion a word of caution is still advisable for clinicians involved in the care of these patients, before considering bleeding in cirrhosis related exclusively to hemodynamic derangements. In fact, the absence of a clear association between hemostasis tests and bleeding, which may suggest that these events are unrelated, is in our opinion not based on strong and unequivocal evidence. Studies were frequently performed on small groups of patients, using different selection criteria and enrolling subjects with variable severity of disease, thus making the results of the different studies hardly comparable. Moreover, the apparently stable balance between coagulant and inhibitory factors present in a compensated patient may be altered by acute and chronic infection, disseminated intravascular coagulation, endotoxemia, renal failure or presence of liver cancer, resulting in a bleeding event [2,13–15]. An even more important and often overlooked issue is the control of bleeding after its initiation, because when patients with advanced disease and severe alteration in hemostasis start to bleed, hemorrhage can be difficult to stop. Along these lines, after the onset of bleeding, consumption phenomena triggered by blood transfusion may alter the coagulation cascade in patients with cirrhosis. A more general issue of great relevance to the clinicians is to what extent in vitro studies can be extrapolated to the in vivo situation, and whether these data, albeit obtained with sound techniques, are sufficient to alter our clinical perception. Several guidelines consider cirrhotic patients at risk for surgery and indicate definite test limits below which aggressive manoeuvers are not recommended [2,16–20]. Despite the absence of controlled studies, platelet transfusion, administration of fresh frozen plasma and antifibrinolytic drugs are still indicated by textbooks and dedicated reviews in selected conditions as an appropriate therapy for coagulation disturbances in cirrhotic patients [1,2,21,22]. In conclusion, clinicians dedicated to liver disease should followwith great attention these latest developments in the field of hemostasis in cirrhotic patients. Nevertheless, before changing our clinical attitude in the everyday clinical management and therapeutic decision-making, more compelling data are needed. Correspondence: Giacomo Laffi, Dipartimento di Medicina Interna, Viale Morgagni 85, I-50134 Florence, Italy. Tel.: +39 55 411643; fax: +39 55 417123; e-mail: g.laffi@dmi.unifi.it 2068 Forum