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Armando Tripodi
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Bleeding, Thrombosis and Vascular Biology
Thrombosis
Is non-alcoholic fatty liver disease a prothrombotic risk factor?
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Invited Editorials
2023-05-19
2023-04-16
2023-04-30
2023-06-27
Bleed Thromb Vascul Biol
Armando Tripodi
2023/05/19
10.4081/btvb.2023.81
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico, Milan; Luigi Villa Foundation, Milan
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Kopec AK, Joshi N, Towery KL, et al. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice. J Pharmacol Exp Ther. 2014; 351:288–97.
Is non-alcoholic fatty liver disease a prothrombotic risk factor?
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                                                                                                             INVITED EDITORIAL

Is non-alcoholic fatty liver disease a prothrombotic risk factor?
Niccolò Bitto,1 Vincenzo La Mura,1,2 Anna Ludovica Fracanzani,2,3 Armando Tripodi1,4
1
 Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico,
Milan; 2Department of Pathophysiology and Transplantation, University of Milan; 3Unit of Internal Medicine and Metabolic Disease,
IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico, Milan; 4Luigi Villa Foundation, Milan, Italy




    The prevalence of non-alcoholic fatty liver disease                            Whether NAFLD acts as an innocent bystander or actively
(NAFLD) in the general population (regardless of ethnicity)                   supports a prothrombotic milieu in different stages of the disease
across the world is steadily increasing, along with the global epi-           is likely but still debated. Indeed, numerous clinical and preclin-
demics of such metabolic diseases as obesity and diabetes. Re-                ical observations have associated the presence of NAFLD with
cently, in a prospective study of a cohort of diabetic patients,              endothelial dysfunction, atherosclerosis, and arterial/venous is-
NAFLD was observed in 65% of the investigated patients, with                  chemic events.2 Moreover, cirrhosis, often observed in patients




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14% having advanced liver fibrosis and 6% cirrhosis.1 NAFLD                   with nonalcoholic steatohepatitis, is associated with a higher in-
represents the hepatic manifestation of a systemic condition as-              cidence of portal vein thrombosis than in other etiologies.3 In




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sociated with the metabolic syndrome, liver-related morbidity                 2014, thrombin generation (TG) was measured in 113 patients
and mortality and, to a greater extent, cardiovascular disease.2              with biopsy-proven metabolic liver disease, ranging from
                                                                              NAFLD to metabolic cirrhosis.4 The ratio of endogenous throm-




                                                                                           e
                                                                              bin potential (ETP) assessed in the presence and absence of


    Correspondence: Niccolò Bitto, Fondazione IRCCS Ca’ Granda
                                                                                    us
                                                                              thrombomodulin (TM) (i.e. ETP-TM-ratio), taken as an index
                                                                              of procoagulant imbalance, was increased even in the non-cir-
                                                                              rhotic stages of the disease. ETP-TM-ratio was further increased
                                                                              al
    Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemo-
                                                                              in cirrhotic patients, and was comparable with that of patients
    philia and Thrombosis Center, Via Pace 9, 20122, Milan, Italy.
                                                                              with cirrhosis of viral etiology.4 Consistent with TG results, there
                                                                    ci

    Email: niccolo.bitto@unimi.it
                                                                              was evidence of a progressive procoagulant imbalance as indi-
                                                                              cated by increased factor VIII (FVIII), one of the main proco-
                                                                  er


    Citation: Bitto N, La Mura V, Fracanzani AL, Tripodi A. Is non-
    alcoholic fatty liver disease a prothrombotic risk factor? Bleeding,      agulants, and decreased protein C (PC), one of the main
                                                                 m



    Thrombosis, and Vascular Biology 2023;2:81.                               anticoagulants. The ratio FVIII/PC is considered one of the de-
                                                                              terminants of the increased TG and the resistance to the antico-
    Key words: NAFLD; thrombin generation; factor VIII; thrombosis.
                                                      om




                                                                              agulant action of TM.5 A subsequent study on smaller numbers
                                                                              of patients did not replicate the data on TG.6 However, results
    Contributions: NB and AT provided the systematic review of liter-
    ature, conceptualization, writing and supervision of the manuscript.      of the two studies were poorly comparable due to differences in
                                               -c




    VLM and ALF writing and supervision of the manuscript.                    experimental TG procedures and the unusually high levels of
                                                                              FVIII in the control group in one of the two studies.6 Further-
                                      on




    Conflict of interest: the authors declare no potential conflict of in-    more, a novel investigation confirmed plasma hypercoagulabil-
    terest.                                                                   ity in patients with NAFLD with a TM-modified TG procedure.7
                                                                              Recently, Valenti et al. evaluated a group of 581 apparently
                                N




    Funding: the study was (partially) supported by the Italian Ministry      healthy blood-donors with metabolic risk factors for the pres-
    of Health – Bando Ricerca Corrente 2022.
                                                                              ence of NAFLD and its potential impact on hemostasis.8 Mark-
    Received: 16 April 2023.                                                  ers of fibrosis were also investigated as indexes of procoagulant
    Accepted: 28 April 2023.                                                  imbalance. NAFLD was diagnosed in 296 of the investigated
                                                                              patients (50%). Elevated von Willebrand factor (VWF) and
    Publisher’s note: all claims expressed in this article are solely those   FVIII correlated with liver fibrosis but not with fat accumulation
    of the authors and do not necessarily represent those of their affili-    in the liver. The latter finding is unsurprising, as in previous
    ated organizations, or those of the publisher, the editors and the re-    studies of patients with NAFLD, the prothrombotic status was
    viewers. Any product that may be evaluated in this article or claim       associated with body mass index and peripheral, rather than he-
    that may be made by its manufacturer is not guaranteed or endorsed        patic fat accumulation.4 Furthermore, predisposition to higher
    by the publisher.
                                                                              VWF and FVIII/PC ratio were independently associated with
    ©
     Copyright: the Author(s), 2023
                                                                              Pro-C3, a specific marker of fibrosis in this population.8 This
    Licensee PAGEPress, Italy                                                 evidence suggests that liver fibrosis in NAFLD can be the result
    Bleeding, Thrombosis and Vascular Biology 2023; 2:81                      of a procoagulant imbalance that could act synergistically to
    doi:10.4081/btvb.2023.81                                                  other known mechanisms such as mitochondrial dysfunction,
                                                                              hepatic stellate cells activations and chronic inflammation.9
    This work is licensed under a Creative Commons Attribution-               Moreover, a diffuse perturbation of the endothelium character-
    NonCommercial 4.0 International License (CC BY-NC 4.0).                   izes patients with metabolic comorbidities and the liver seems
                                                                              no exception.10 Therefore, the development of fibrosis in


                                                Bleeding, Thrombosis and Vascular Biology 2023; 2:81
                                     Is non-alcoholic fatty liver disease a prothrombotic risk factor?                                     3




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Figure 1. The vicious circle between procoagulant imbalance and fibrosis development in the evolution from nonalcoholic fatty-liver
disease to cirrhosis, impacting cardiovascular and liver related events.
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NAFLD, in addition to hypercoagulability, endothelial pertur-            and thrombotic tendency is steadily growing, particularly when
bation, and reduced blood flow (collectively known as the Vir-           fibrosis is present. This represents a starting point for a research
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chow’s triad), may contribute to an increased risk of                    agenda sought to fill the gap from experimental evidence of the
thrombosis.11 This notwithstanding, NAFLD is probably undi-              noxious hypercoagulability/metabolic axis to bedside interven-
agnosed in the absence of an active search policy, because it can        tions aimed at reducing the cardiovascular, thrombotic and liver-
                                -c




be asymptomatic unless decompensated cirrhosis develops. Al-             related burden associated to this mounting pandemic.
though the need for NAFLD screening in the general population
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is debated, diagnosis of this condition in high-risk patients could
enable to early detect subjects at risk of both vascular prothrom-       References
botic events and life-threating complications associated with the
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liver disease (e.g., hepato-cellular carcinoma and acute variceal         1. Ajmera V, Cepin S, Tesfai K, et al. A prospective study on
bleeding) (Figure 1). For the same reason, we believe that the               the prevalence of NAFLD, advanced fibrosis, cirrhosis and
efficacy of a hepatological screening in the setting of patients             hepatocellular carcinoma in people with type 2 diabetes. J
with metabolic disease, arterial or venous thrombotic events,                Hepatol 2022;78:471-8.
should be advisable. All the above observations deserve a po-             2. Anstee QM, Targher G, Day CP. Progression of NAFLD to
tential practical consequence since the prothrombotic imbalance              diabetes mellitus, cardiovascular disease or cirrhosis. Nat
observed in NAFLD could be the premise to undertake antico-                  Rev Gastroenterol Amp Hepatol 2013;10:330-45.
agulation as a potential preventive strategy. Notably, in 2014            3. Stine JG, Argo CK, Pelletier SJ, et al. Advanced non-alco-
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(HFD).12 Importantly, thrombin inhibition by dabigatran pre-                 imbalance in patients with non-alcoholic fatty liver disease.
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these observations support new studies exploring the potential               ratio of values with-to-without thrombomodulin. Thromb
value of hemostasis as target of therapy in NAFLD. In conclu-                Haemost 2017;117:830-6.
sion, the relevance of NAFLD in determining hypercoagulability            6. Potze W, Siddiqui MS, Boyett SL, et al. Preserved hemosta-


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4                                                              N. Bitto et al.




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   2020;123:190-7.                                                        11. Tripodi A, Lombardi R, Primignani M, et al. Hypercoagula-
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   2022;4:100598.                                                         12. Kopec AK, Joshi N, Towery KL, et al. Thrombin inhibition
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                                         Bleeding, Thrombosis and Vascular Biology 2023; 2:81
