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Increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death

Published:March 29, 2022DOI:https://doi.org/10.1016/j.jhep.2022.03.009

      Highlights

      • We assessed whole blood platelet aggregation in cirrhosis by means of a PLT ratio.
      • Patients with cirrhosis have a higher PLT ratio than those with chronic hepatitis/healthy individuals.
      • PLT ratio increases significantly with severity of cirrhosis (Child-Pugh C>B>A).
      • In decompensated patients, PLT ratio is associated with progression of cirrhosis.

      Background & Aims

      Studies on platelet aggregation in cirrhosis are controversial because interpretation of platelet function is challenged by thrombocytopenia. We conducted a prospective study to investigate whole blood platelet aggregation in cirrhosis and its association with liver-related outcomes.

      Methods

      Platelet aggregation was assessed by whole blood aggregometry (Multiplate®). To overcome the influence of platelet count and compare cirrhosis with thrombocytopenia vs. controls with normal platelet count, we calculated a ratio between platelet aggregation and platelet count (PLT ratio). Then, we prospectively followed patients with cirrhosis and ascertained predictors of decompensation, transplantation, and death.

      Results

      Two-hundred and three patients with cirrhosis were prospectively recruited (77% decompensated). PLT ratio was significantly higher in cirrhosis than in those with chronic hepatitis and healthy individuals (0.44 vs. 0.25 and 0.26, respectively; p <0.0001). In cirrhosis, the ratio increased with disease severity (Child-Pugh class C>B>A) and was particularly elevated in decompensated patients with severe thrombocytopenia. Among decompensated patients, 65 had further decompensation, underwent transplantation, or died during a 6-month follow-up. On multivariate analysis, PLT ratio (odds ratio 1.87; 95% CI 1.23-2.84; p = 0.003) and MELD score (odds ratio 1.05; 95% CI 1.01-1.08; p = 0.01) were independently associated with outcome. The relative risk of events was 7.5-fold higher in patients with PLT ratio >0.75 vs. patients with PLT ratio <0.25 (95% CI 2.5-21.9; p = 0.003). The increased PLT ratio, its discriminative ability for composite outcome, and the prognostic value of PLT ratio >0.75 were confirmed in an independent cohort of hospitalized patients with decompensated cirrhosis (n = 41).

      Conclusions

      Patients with cirrhosis, particularly when decompensated, exhibit significantly increased whole blood platelet aggregation. Decompensated patients with a PLT ratio >0.75 have a >80% probability of further decompensation, transplantation, or liver-related death within 6 months.

      Lay summary

      In patients with cirrhosis, previous studies have suggested that platelets (i.e. circulating blood cells that help form clots to stop bleeding) are dysfunctional. In particular, these studies suggested that platelet aggregation (the process by which platelets adhere to each other to form clots) is reduced. Since platelet aggregation is important for clot formation, it has been hypothesized that alterations of platelet aggregation may be responsible for the increased risk of bleeding observed in patients with cirrhosis. Our study demonstrates: i) that platelet aggregation in patients with cirrhosis is higher than in healthy individuals; ii) that platelet aggregation in patients with decompensated cirrhosis (i.e. those who have already experienced some complications of cirrhosis) is particularly elevated and associated with risk of further complications and death.

      Graphical abstract

      Keywords

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      References

        • Desborough M.J.
        • Hockley B.
        • Sekhar M.
        • Burroughs A.K.
        • Stanworth S.J.
        • Jairath V.
        • et al.
        Patterns of blood component use in cirrhosis: a nationwide study.
        Liver Int. 2016; 36: 522-529
        • Basili S.
        • Raparelli V.
        • Napoleone L.
        • Talerico G.
        • Corazza G.R.
        • Perticone F.
        • et al.
        Platelet count does not predict bleeding in cirrhotic patients: results from the PRO-LIVER study.
        Am J Gastroenterol. 2018; 113: 368-375
        • Zanetto A.
        • Rinder H.M.
        • Senzolo M.
        • Simioni P.
        • Garcia-Tsao G.
        Reduced clot stability by thromboelastography as a potential indicator of procedure-related bleeding in decompensated cirrhosis.
        Hepatol Commun. 2021; 5: 272-282
        • Northup P.G.
        • Garcia-Pagan J.C.
        • Garcia-Tsao G.
        • Intagliata N.M.
        • Superina R.A.
        • Roberts L.N.
        • et al.
        Vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease: 2020 practice guidance by the American Association for the Study of Liver Diseases.
        Hepatology. 2021; 73: 366-413
        • Roberts L.N.
        • Lisman T.
        • Stanworth S.
        • Hernandez-Gea V.
        • Magnusson M.
        • Tripodi A.
        • et al.
        Periprocedural management of abnormal coagulation parameters and thrombocytopenia in patients with cirrhosis: guidance from the SSC of the ISTH.
        J Thromb Haemost. 2021;
        • Russo F.P.
        • Zanetto A.
        • Campello E.
        • Bulato C.
        • Shalaby S.
        • Spiezia L.
        • et al.
        Reversal of hypercoagulability in patients with HCV-related cirrhosis after treatment with direct-acting antivirals.
        Liver Int. 2018; 38: 2210-2218
        • Zanetto A.
        • Rinder H.M.
        • Campello E.
        • Saggiorato G.
        • Deng Y.
        • Ciarleglio M.
        • et al.
        Acute kidney injury in decompensated cirrhosis is associated with both hypo-coagulable and hyper-coagulable features.
        Hepatology. 2020; 72: 1327-1340
        • Zanetto A.
        • Rodriguez-Kastro K.I.
        • Germani G.
        • Ferrarese A.
        • Cillo U.
        • Burra P.
        • et al.
        Mortality in liver transplant recipients with portal vein thrombosis - an updated meta-analysis.
        Transpl Int. 2018; 31: 1318-1329
        • Senzolo M.
        • Garcia-Tsao G.
        • Garcia-Pagan J.C.
        Current knowledge and management of portal vein thrombosis in cirrhosis.
        J Hepatol. 2021; 75: 442-453
        • Noronha Ferreira C.
        • Marinho R.T.
        • Cortez-Pinto H.
        • Ferreira P.
        • Dias M.S.
        • Vasconcelos M.
        • et al.
        Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: a prospective study.
        Liver Int. 2019; 39: 1459-1467
        • Turon F.
        • Driever E.G.
        • Baiges A.
        • Cerda E.
        • Garcia-Criado A.
        • Gilabert R.
        • et al.
        Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and hemostatic factors.
        J Hepatol. 2021; 75: 1367-1376
        • Zermatten M.G.
        • Fraga M.
        • Moradpour D.
        • Bertaggia Calderara D.
        • Aliotta A.
        • Stirnimann G.
        • et al.
        Hemostatic alterations in patients with cirrhosis: from primary hemostasis to fibrinolysis.
        Hepatology. 2020; 71: 2135-2148
        • Raparelli V.
        • Basili S.
        • Carnevale R.
        • Napoleone L.
        • Del Ben M.
        • Nocella C.
        • et al.
        Low-grade endotoxemia and platelet activation in cirrhosis.
        Hepatology. 2017; 65: 571-581
        • Lisman T.
        • Porte R.J.
        Pitfalls in assessing platelet activation status in patients with liver disease.
        Liver Int. 2012; 32 (author reply 1028): 1027
        • Zanetto A.
        • Senzolo M.
        • Blasi A.
        Perioperative management of antithrombotic treatment.
        Best Pract Res Clin Anaesthesiol. 2020; 34: 35-50
        • Koltai K.
        • Kesmarky G.
        • Feher G.
        • Tibold A.
        • Toth K.
        Platelet aggregometry testing: molecular mechanisms, techniques and clinical implications.
        Int J Mol Sci. 2017; 18
        • Soliman M.
        • Hartmann M.
        Multiplate® platelet aggregation findings are dependent on platelet count but can be corrected by use of a ratio.
        Appl Sci. 2020; 10: 7971
        • Primignani M.
        • Tosetti G.
        • Tripodi A.
        Implementing pre-procedural thrombopoietin receptor agonists in cirrhotic patients with severe thrombocytopenia: indiscriminate, selective or unneeded?.
        Dig Liver Dis. 2021; 53: 1394-1395
        • Kopec A.K.
        • Joshi N.
        • Luyendyk J.P.
        Role of hemostatic factors in hepatic injury and disease: animal models de-liver.
        J Thromb Haemost. 2016; 14: 1337-1349
        • de Franchis R.
        • Bosch J.
        • Garcia-Tsao G.
        • Reiberger T.
        • Ripoll C.
        Baveno VII - renewing consensus in portal hypertension.
        J Hepatol. 2021;
        • Garcia-Tsao G.
        • Abraldes J.G.
        • Berzigotti A.
        • Bosch J.
        Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.
        Hepatology. 2017; 65: 310-335
        • Schulman S.
        • Kearon C.
        Subcommittee on Control of Anticoagulation of the S, Standardization Committee of the International Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
        J Thromb Haemost. 2005; 3: 692-694
        • Moreau R.
        • Jalan R.
        • Gines P.
        • Pavesi M.
        • Angeli P.
        • Cordoba J.
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144 (1437 e1421-1429): 1426-1437
        • D’Amico G.
        Natural history and stages of cirrhosis.
        in: De Franchis R. Dell’Era A. Variceal hemorrhage. Springer-Verlag, New York2014 2014
        • Zanetto A.
        • Senzolo M.
        • Campello E.
        • Bulato C.
        • Gavasso S.
        • Shalaby S.
        • et al.
        Influence of hepatocellular carcinoma on platelet aggregation in cirrhosis.
        Cancers (Basel). 2021; 13
        • European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L
        EASL clinical practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Angeli P.
        • Gines P.
        • Wong F.
        • Bernardi M.
        • Boyer T.D.
        • Gerbes A.
        • et al.
        Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
        Gut. 2015; 64: 531-537
        • Zanetto A.
        • Campello E.
        • Bulato C.
        • Gavasso S.
        • Saggiorato G.
        • Shalaby S.
        • et al.
        More pronounced hypercoagulable state and hypofibrinolysis in patients with cirrhosis with versus without HCC.
        Hepatol Commun. 2021;
        • Nadal E.
        • Simioni P.
        • Spiezia L.
        • Angeli P.
        • Fasolato S.
        • Zanetto A.
        • et al.
        Thromboelastographic evaluation of hemostatic balance in cirrhotic patients with infection.
        Dig Liv Dis. 2017; 49
        • Lisman T.
        • Porte R.J.
        Platelet function in patients with cirrhosis.
        J Hepatol. 2012; 56 (author reply 994-995): 993-994
        • Lisman T.
        • Bongers T.N.
        • Adelmeijer J.
        • Janssen H.L.
        • de Maat M.P.
        • de Groot P.G.
        • et al.
        Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.
        Hepatology. 2006; 44: 53-61
        • Campello E.
        • Zanetto A.
        • Bulato C.
        • Maggiolo S.
        • Spiezia L.
        • Russo F.P.
        • et al.
        Coagulopathy is not predictive of bleeding in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.
        Liver Int. 2021; 41: 2455-2466
        • Jepsen P.
        • Tapper E.B.
        • Deleuran T.
        • Kazankov K.
        • Askgaard G.
        • Sorensen H.T.
        • et al.
        Risk and outcome of venous and arterial thrombosis in patients with cirrhosis: a Danish nation-wide cohort study.
        Hepatology. 2021; 74: 2725-2734
        • McHutchison J.G.
        • Dusheiko G.
        • Shiffman M.L.
        • Rodriguez-Torres M.
        • Sigal S.
        • Bourliere M.
        • et al.
        Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C.
        N Engl J Med. 2007; 357: 2227-2236
        • Soliman M.
        • Hartmann M.
        Impedance aggregometry reveals increased platelet aggregation during liver transplantation.
        J Clin Med. 2019; 8
        • Smyth S.S.
        • McEver R.P.
        • Weyrich A.S.
        • Morrell C.N.
        • Hoffman M.R.
        • Arepally G.M.
        • et al.
        Platelet functions beyond hemostasis.
        J Thromb Haemost. 2009; 7: 1759-1766
        • Lisman T.
        • Luyendyk J.P.
        Platelets as modulators of liver diseases.
        Semin Thromb Hemost. 2018; 44: 114-125
        • Engelmann C.
        • Claria J.
        • Szabo G.
        • Bosch J.
        • Bernardi M.
        Pathophysiology of decompensated cirrhosis: portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction.
        J Hepatol. 2021; 75: S49-S66