- Email: [email protected]
Coagulopathy in cirrhosis – The role of the platelet in hemostasis
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: [email protected] (R. Malik)
Platelets play an important role in coagulation balance of cirrhotic patients
Inflammation Disease specific: • Viral hepatitis • Autoimmunity • Metabolic liver disease • Endotoxin
Quantitative defects • Splenic pooling • Low thrombopoietin • Antiplatelet antibodies
Nucleotides Platelets
Coagulation disturbances in cirrhosis
Microparticles
IXa
Qualitative functional defects of cirrhosis and uremia
IXa
IX XIa
II
X
Va
IIa
Xa
VIIIa
Activated platelet
<60,000 platelets
>60,000 platelets
Thrombin generation
Low levels of factors II, V, VII, IX, X and XI
Elevated level of factor VIII Low levels of protein C, protein S, antithrombin and, heparin co-factor II
COAGULATION BALANCE
BLEEDING
THROMBOSIS
Cirrhosis is characterized by a dynamic, precarious hemostatic balance
Coagulation balance
Clinical event: e.g. hepatoma development
Thrombosis
Hemostasis
Heathy patients
Bleeding
Cirrhosis
Time
Clinical event: e.g. bacterial peritonitis/infection
Keywords: Thrombosis; Bleeding; Endotoxin; Portal hypertension. Received 28 November 2012; received in revised form 4 March 2013; accepted 5 March 2013 Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanine monophosphate.
Journal of Hepatology 2013 vol. 59 | 889–890
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-àvis portosystemic shunting and gut barrier disruption [1,12]. Platelet890
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. All rights reserved.
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.
References [1] Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? J Hepatol. 2011;55:1415–1427. [2] Afdhal NH, Giannini EG, Tayyab G, Mohsin A, Lee JW, Andriulli A, et al., Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012;367:716–724 [3] Tripodi A, Primignani M, Chantarangkul V, Dell’Era A, Clerici M, de Franchis R, et al., An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology. 2009;137:2105–2111. [4] Tripodi A, Primignani M, Chantarangkul V, Clerici M, Dell’Era A, Fabris F, et al., Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology. 2006;44:440–445. [5] Ordinas A, Escolar G, Cirera I, Viñas M, Cobo F, Bosch J, et al., Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions. Hepatology. 1996;24:1137–1142. [6] Blake JC, Sprengers D, Grech P, McCormick PA, McIntyre N, Burroughs AK. Bleeding time in patients with hepatic cirrhosis. BMJ. 1990;301:12–15. [7] Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, et al., Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006;44:53–61. [8] Thomas DP, Ream VJ, Stuart RK. Platelet aggregation in patients with Laennec’s cirrhosis of the liver. N Engl J Med. 1967;276:1344–1348. [9] Witters P, Freson K, Verslype C, Peerlinck K, Hoylaerts M, Nevens F, et al., Review article: blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther. 2008;27:1017–1029. [10] Enjyoji K, Sévigny J, Lin Y, Frenette PS, Christie PD, Esch JS 2nd, et al., Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med. 1999;5:1010–1017. [11] Laffi G, Marra F, Failli P, Ruggiero M, Cecchi E, Carloni V, et al., Defective signal transduction in platelets from cirrhotics is associated with increased cyclic nucleotides. Gastroenterology. 1993;105:148–156. [12] Sayed D, Amin NF, Galal GM. Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis.Thromb Res. 2010 May;125:e228–233. [13] Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, et al., Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143:1253–1260.
Journal of Hepatology 2013 vol. 59 | 889–890
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: [email protected] (R. Malik)
Platelets play an important role in coagulation balance of cirrhotic patients
Inflammation Disease specific: • Viral hepatitis • Autoimmunity • Metabolic liver disease • Endotoxin
Quantitative defects • Splenic pooling • Low thrombopoietin • Antiplatelet antibodies
Nucleotides Platelets
Coagulation disturbances in cirrhosis
Microparticles
IXa
Qualitative functional defects of cirrhosis and uremia
IXa
IX XIa
II
X
Va
IIa
Xa
VIIIa
Activated platelet
<60,000 platelets
>60,000 platelets
Thrombin generation
Low levels of factors II, V, VII, IX, X and XI
Elevated level of factor VIII Low levels of protein C, protein S, antithrombin and, heparin co-factor II
COAGULATION BALANCE
BLEEDING
THROMBOSIS
Cirrhosis is characterized by a dynamic, precarious hemostatic balance
Coagulation balance
Clinical event: e.g. hepatoma development
Thrombosis
Hemostasis
Heathy patients
Bleeding
Cirrhosis
Time
Clinical event: e.g. bacterial peritonitis/infection
Keywords: Thrombosis; Bleeding; Endotoxin; Portal hypertension. Received 28 November 2012; received in revised form 4 March 2013; accepted 5 March 2013 Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanine monophosphate.
Journal of Hepatology 2013 vol. 59 | 889–890
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-àvis portosystemic shunting and gut barrier disruption [1,12]. Platelet890
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. All rights reserved.
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.
References [1] Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? J Hepatol. 2011;55:1415–1427. [2] Afdhal NH, Giannini EG, Tayyab G, Mohsin A, Lee JW, Andriulli A, et al., Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012;367:716–724 [3] Tripodi A, Primignani M, Chantarangkul V, Dell’Era A, Clerici M, de Franchis R, et al., An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology. 2009;137:2105–2111. [4] Tripodi A, Primignani M, Chantarangkul V, Clerici M, Dell’Era A, Fabris F, et al., Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology. 2006;44:440–445. [5] Ordinas A, Escolar G, Cirera I, Viñas M, Cobo F, Bosch J, et al., Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions. Hepatology. 1996;24:1137–1142. [6] Blake JC, Sprengers D, Grech P, McCormick PA, McIntyre N, Burroughs AK. Bleeding time in patients with hepatic cirrhosis. BMJ. 1990;301:12–15. [7] Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, et al., Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006;44:53–61. [8] Thomas DP, Ream VJ, Stuart RK. Platelet aggregation in patients with Laennec’s cirrhosis of the liver. N Engl J Med. 1967;276:1344–1348. [9] Witters P, Freson K, Verslype C, Peerlinck K, Hoylaerts M, Nevens F, et al., Review article: blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther. 2008;27:1017–1029. [10] Enjyoji K, Sévigny J, Lin Y, Frenette PS, Christie PD, Esch JS 2nd, et al., Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med. 1999;5:1010–1017. [11] Laffi G, Marra F, Failli P, Ruggiero M, Cecchi E, Carloni V, et al., Defective signal transduction in platelets from cirrhotics is associated with increased cyclic nucleotides. Gastroenterology. 1993;105:148–156. [12] Sayed D, Amin NF, Galal GM. Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis.Thromb Res. 2010 May;125:e228–233. [13] Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, et al., Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143:1253–1260.
Journal of Hepatology 2013 vol. 59 | 889–890