Hepatology Snapshot

Coagulopathy in cirrhosis: The role of the platelet in hemostasis

Elliot B. Tapper, Simon C. Robson, Raza Malik*

Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA*Corresponding author. Address: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue

Boston, MA 02215, USA. Tel.: +1 617 632 1063; Fax.: +1 617 632 1065. *E-mail address: rmalik@bidmc.harvard.edu (R. Malik)

Keywords: Thrombosis; Bleeding; Endotoxin; Portal hypertension.Received 28 November 2012; received in revised form 4 March 2013; accepted 5 March 2013

Journal of Hepatology 2013 vol. 59 | 889–890

Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanine monophosphate.

Cirrhosis is characterized by a dynamic, precarioushemostatic balance

Platelets play an important role incoagulation balance of cirrhotic patients

COAGULATION BALANCE

InflammationDisease specific:• Viral hepatitis• Autoimmunity• Metabolic liver disease• Endotoxin

Quantitative defects• Splenic pooling• Low thrombopoietin• Antiplatelet antibodies

Nucleotides

Microparticles

Coagulation disturbancesin cirrhosis

<60,000platelets

>60,000 platelets

Low levels of factorsII, V, VII, IX, X and XI

Elevated level of factor VIIILow levels of protein C,

protein S, antithrombin and, heparin co-factor II

Platelets

Clinical event: e.g. bacterial peritonitis/infection

Coa

gula

tion

bala

nce

Time

Thrombosis

Hemostasis

Bleeding

Heathy patients

Cirrhosis

Clinical event: e.g. hepatoma development

Qualitative functional defects

of cirrhosis and uremia

THROMBOSISBLEEDING

Activated platelet

VIIIa

IX

XIa

X II

IIaXa

IXa

IXa

Thrombin generation

Va

Open access under CC BY-NC-ND license.

Hepatology Snapshot

Cirrhotic patients are at increased risk of bleeding, particularly gastrointestinal bleeding, as a consequence of portal hypertension and/or coagulopathy attributed to liver synthetic dysfunction. Paradoxically, they are also at risk of thrombosis, predominantly in the splanchnic circulation, especially when platelet counts are increased by transfusion or drug therapy [1,2]. A major problem in clinical practice is the inadequacy of coagulation tests, which do not predict bleeding or thrombotic events, but may result in the inappropriate administration of therapies (e.g., plasma transfusions prior to procedures). Additionally, these tests cannot provide information on the dynamic interaction between the coagulation and anticoagulation pathways. Evidence is mounting to highlight the central role of the platelet, of which the quantitative and qualitative properties may determine the dynamic hemostatic forces in cirrhosis. Cirrhotic thrombocytopenia and platelet dysfunction are multifactorial with many simultaneous contributions [1]. Portal hypertension leads to splenic pooling, sequestering platelets from the circulation. Portosystemic shunting and gut barrier disruption result in endotoxaemia with systemic immune activation, antiplatelet antibody production, aberrant fibronolysis, and activation of coagulation with platelet consumption [1]. Cirrhosis and decreased functional liver mass result in lower thrombopoetin levels and platelet underproduction. There are 3 phases of clotting in which platelets play a crucial role: primary hemostasis (platelet-vessel wall interactions), coagulation (thrombin generation), and fibrinolysis (clot dissolution). In general, thrombocytopenia, with a reduced number of functional platelets, appears to impact blood coagulation the most, by limiting thrombin generation. Despite prolonged prothrombin times, thrombin generation appears to be maintained in cirrhosis as a result of protein C deficiency [3]. Using techniques that assess protein C activity, cirrhotic plasma appears hypercoagulable until severe thrombocytopenia occurs. In vitro studies of platelet-rich plasma from cirrhotic patients support normal thrombin generation if platelets are at least 60,000 [4]. Interestingly, disturbing the new procoagulant and anticoagulant balance in cirrhosis, by raising platelet counts using pharmacological therapy (e.g., eltrombopag), increases the risk of thrombosis, mainly in the portal circulation [2]. Qualitative platelet defects in cirrhosis are dynamic and reflect the patient’s overall health. They manifest in each step of the multiphasic platelet-vessel wall interaction: adhesion, aggregation, and activation. Adhesion: compared to healthy patients, cirrhotic platelet adherence to the subendothelium of injured vessels is defective, akin to that observed in uremia [5]. A weak but significant correlation exists between the platelet count and bleeding time [6]. The correlation is weak as platelet defects are partially compensated by a concomitant increase in the adhesive protein von Willebrand factor [7]. Aggregation: in response to any number of stimuli – ADP, thrombin, collagen, epinephrine, or ristocetin – the degree of platelet aggregation is significantly less in cirrhosis compared to healthy controls [8]. Activation: the cirrhotic platelet is said to be ‘exhausted,’ exhibiting reduced transmembrane signaling and a progressive inability to activate in response to appropriate stimuli. Many reasons account for this observation: (i) cirrhotic platelets have a ‘storage pool defect’ whereby dense granule concentrations of prothrombotic signaling molecules (e.g., platelet factor 4, beta-thromboglobulin, and serotonin) are abnormally low; (ii) cirrhotic platelets secrete disproportionately high levels of ATP. Excess extracellular ATP antagonizes ADP-induced activation of receptor P2Y12 (i.e., clopidogrel’s target) and desensitizes P2Y1 resulting in lower intraplatelet ionized calcium levels [9,10]; (iii) there is an intraplatelet accumulation of inhibitory messengers (cyclic nucleotides), sharply limiting phospholipase activity, resulting in lower concentrations of inositol phosphate and calcium [11]. The end-result is platelets that produce less thromboxane and serotonin, precipitating cascading defects in platelet aggregation [9]. Each qualitative platelet defect is progressive with increasing Child’s class. This allows us to generate hypotheses regarding underlying mechanisms. Diminished intrinsic liver function, however, will not suffice, as features of cirrhotic coagulopathy can be seen in non-cirrhotic patients with portal vein thrombosis or other causes of extrahepatic portal hypertension. Qualitative platelet defects are likely reflective of increased bloodstream endotoxin concentration vis-à-vis portosystemic shunting and gut barrier disruption [1,12]. Platelet-

derived microparticles, in turn, are increased in cirrhosis as a function of systemic inflammation. Microparticles have a known procoagulant effect and may play an important role in the relative hypercoagulability of early cirrhosis [12]. The literature offers a number of strategies that may reduce endotoxin load or the effects of the consequent inflammation: gut decontamination (e.g., rifaximin), treatment of intrahepatic endothelial dysfunction (e.g., antioxidants) or prevention of gut bacterial translocation (e.g., beta blockers, anticoagulants). A recent trial of enoxaparin in highly selected non-thrombocytopenic cirrhotics has shown dramatic reductions in the frequency of hepatic decompensation. This landmark study may reverse dogma, should further investigation confirm that anticoagulation reduces bacterial translocation and microthrombi in the hepatic circulation, improving liver function in this selected population [13]. It is yet to be determined if this is a viable therapeutic option in more advanced liver disease without promoting bleeding. In summary, in cirrhosis, the normal homeostatic reserve capacity to control bleeding and thrombosis events is lost, with the predilection toward bleeding or thrombosis dependent on the individual and the precipitant. Evidence is emerging on the central role of the platelet in this process.© 2013 European Association for the Study of the Liver. Published by Elsevier B.V.

Conflict of interest

The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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Journal of Hepatology 2013 vol. 59 | 889–890890