Patients with liver diseases acquire complex alterations in their hemostatic system that may lead to abnormalities in routine diagnostic test of hemostasis. Thrombocytopenia, prolongations in the prothrombin time and activated partial thromboplastin time, and decreased plasma fibrinogen are common in patients with advanced liver disease. Historically, liver diseases therefore have been classified as an acquired bleeding disorder. Laboratory and clinical observations have demonstrated that although routine diagnostic tests of hemostasis suggest a hypocoagulable state, patients with liver disease also tend to develop thrombotic events. Overall, patients have commensurate changes in both pro- and antihemostatic pathways. This new hemostatic balance, however, appears much more fragile than the hemostatic balance in individuals with normal liver function, and patients with liver disease can readily experience both hemostasis-related bleeding and thrombotic events. These insights into the hemostatic balance in patients with liver disease have led to revised recommendations for clinical management of hemostasis. In 2020, an SSC working group within the ISTH has been founded with the aim to disseminate new concepts on prevention and treatment of bleeding and thrombosis in patients with liver disease. The current document will outline the hemostatic changes in patients with liver disease, the limitations of routine diagnostic tests of hemostasis, and the concept of rebalanced hemostasis.© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

A simple waterfall sequence is proposed to explain the function of the various protein clotting factors during the formation of the fibrin clot. When clotting is initiated, each cloting factor except fibrinogen is converted to a form that has enzymatic activity. This activation occurs in a sepwise sequence with each newly formed enzyme reacting with its specific substrate, converting it to an active enzyme.

The concept of coagulation as a "cascade" of proteolytic reactions was a conceptual breakthrough in understanding how the coagulation process acts as a biologic amplifier. The model that it evolved into, with "extrinsic" and "intrinsic" pathways meeting in a common pathway, delineates the interactions between the coagulation proteins and provides a framework for interpreting the common screening coagulation tests. The coagulation "cascade" has significant limitations as a model of how hemostasis occurs in vivo, however. This article describes how the modern view of hemostasis has evolved to emphasize the role of cells in controlling and directing the coagulation reactions. It also highlights how host factors that are not part of the coagulation process per se can influence the effectiveness of coagulation.

Thrombosis is the most frequent cause of mortality worldwide and is closely linked to haemostasis, which is the biological mechanism that stops bleeding after the injury of blood vessels. Indeed, both processes share the core pathways of blood coagulation and platelet activation. Here, we summarize recent work suggesting that thrombosis under certain circumstances has a major physiological role in immune defence, and we introduce the term immunothrombosis to describe this process. Immunothrombosis designates an innate immune response induced by the formation of thrombi inside blood vessels, in particular in microvessels. Immunothrombosis is supported by immune cells and by specific thrombosis-related molecules and generates an intravascular scaffold that facilitates the recognition, containment and destruction of pathogens, thereby protecting host integrity without inducing major collateral damage to the host. However, if uncontrolled, immunothrombosis is a major biological process fostering the pathologies associated with thrombosis.

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.

The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively “silenced” by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease.

Quantitative abnormalities in factor VIII (FVIII) and its binding partner, von Willebrand factor (VWF), are associated with an increased risk for bleeding or thrombosis and pathways that regulate the clearance of VWF-FVIII can strongly influence their plasma levels. In 2010, the CHARGE genome-wide association study (GWAS) meta-analysis identified variants in the genes for the sinusoidal endothelial receptors CLEC4M, stabilin-2, and SCARA5 as being associated with plasma levels of VWF and/or FVIII in normal individuals. The ability of these receptors to bind, internalize, and clear the VWF-FVIII complex from the circulation has now been reported in a series of studies utilizing in vitro and in vivo models. The receptor stabilin-2 has also been shown to modulate the immune response to infused VWF-FVIII concentrates in a murine model. In addition, the influence of genetic variants in CLEC4M, STAB2, and SCARA5 on type 1 VWD/low VWF phenotype, FVIII pharmacokinetics, and the risk for venous thromboembolism have been described in a number of patient-based studies. Understanding the role of these receptors in the regulation of VWF-FVIII clearance has led to significant insights into the genomic architecture that modulates plasma VWF and FVIII levels, improving the understanding of pathways that regulate VWF-FVIII clearance and the mechanistic basis of quantitative VWF-FVIII pathologies.Copyright © 2023. Published by Elsevier Inc.

Nonalcoholic steatohepatitis (NASH) is a disorder that consists of steatosis and hepatic inflammation. It is not known why only some people with steatosis develop NASH. Recently, we identified dietary cholesterol as a factor that directly leads to hepatic inflammation and hepatic foam cell formation. We propose a mechanism by which Kupffer cells (KCs) take up modified cholesterol-rich lipoproteins via scavenger receptors (SRs). KCs thereby accumulate cholesterol, become activated, and may then trigger an inflammatory reaction. Scavenging of modified lipoproteins mainly depends on CD36 and macrophage scavenger receptor 1.To evaluate the involvement of SR-mediated uptake of modified lipoproteins by KCs in the development of diet-induced NASH, female low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice were lethally irradiated and transplanted with bone marrow from Msr1(+/+)/Cd36(+/+)or Msr1(-/-)/Cd36(-/-) mice and fed a Western diet.Macrophage and neutrophil infiltration revealed that hepatic inflammation was substantially reduced by approximately 30% in Msr1(-/-)/Cd36(-/-)-transplanted mice compared with control mice. Consistent with this, the expression levels of well-known inflammatory mediators were reduced. Apoptotis and fibrosis were less pronounced in Msr1(-/-)/Cd36(-/-)-transplanted mice, in addition to the protective phenotype of natural antibodies against oxidized low-density lipoprotein in the plasma. Surprisingly, the effect on hepatic inflammation was independent of foam cell formation.Targeted inactivation of SR pathways reduces the hepatic inflammation and tissue destruction associated with NASH, independent of hepatic foam cell formation.Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

The function of the liver as an important constituent of the immune system involved in innate as well as adaptive immunity is warranted by different highly specialized cell populations. As the major source of acute phase proteins, including secreted pathogen recognition receptors (PRRs), short pentraxins, components of the complement system or regulators of iron metabolism, hepatocytes are essential constituents of innate immunity and largely contribute to the control of a systemic inflammatory response. The production of acute phase proteins in hepatocytes is controlled by a variety of different cytokines released during the inflammatory process with IL-1- and IL-6-type cytokines as the leading regulators operating both as a cascade and as a network having additive, inhibitory, or synergistic regulatory effects on acute phase protein expression. Hence, IL-1β substantially modifies IL-6-induced acute phase protein production as it almost completely abrogates production of acute phase proteins such as γ-fibrinogen, α(2)-macroglobulin or α(1)-antichymotrypsin, whereas production of for example hepcidin, C-reactive protein and serum amyloid A is strongly up-regulated. This switch-like regulation of IL-6-induced acute phase protein production by IL-1β is due to a complex processing of the intracellular signaling events activated in response to IL-6 and/or IL-1β, with the crosstalk between STAT3- and NF-κB-mediated signal transduction being of particular importance. Recent data suggest that in this context complex formation between STAT3 and the p65 subunit of NF-κB might be of key importance. The present review summarizes the regulation of acute phase protein production focusing on the role of the crosstalk of STAT3- and NF-κB-driven pathways for transcriptional control of acute phase gene expression.Copyright © 2011 Elsevier GmbH. All rights reserved.

Advancements in the conceptual thinking of haemostasis and thrombosis have been catalysed by major developments within health research over several decades. The cascade model of coagulation was first described in the 1960s when biochemistry gained prominence through innovative experimentation and technical developments. This was followed by the cell-based model which integrated cellular coordination to the enzymology of clot formation, and was conceptualised during the growth period in cell biology at the turn of the millennium. Each step forward has heralded a revolution in clinical therapeutics, both in procoagulant and anticoagulant treatments to improve patient care. In current times, the COVID19 pandemic may also prove to be a catalyst - thrombotic challenges including the mixed responses to anticoagulant treatment and the vaccine-induced immune thrombotic thrombocytopenia have exposed limitations in our pre-existing concepts whilst simultaneously demanding novel therapeutic approaches. It is increasingly clear that innate immune activation as part of the host response to injury is not separate but integrated into adaptive clot formation. Our review summarises current understanding of the major molecules facilitating such a cross-talk between immunity, inflammation and coagulation. We demonstrate how such effects can be layered upon the cascade and cell-based models to evolve conceptual understanding of the physiology of immunohaemostasis and the pathology of immunothrombosis.Copyright © 2023 American Society of Hematology.

Patients with cirrhosis develop complex alterations in primary hemostasis that include both hypocoagulable and hypercoagulable features. This includes thrombocytopenia, multiple alterations of platelet function, and increased plasma levels of von Willebrand factor. Contrary to the historical view that platelet dysfunction in cirrhosis might be responsible for an increased bleeding tendency, the current theory posits a rebalanced hemostasis in patients with cirrhosis. Severe thrombocytopenia is not indicative of the bleeding risk in patients undergoing invasive procedures and does not dictate per se the need for pre-procedural prophylaxis. A more comprehensive and individualized risk assessment should combine hemostatic impairment, the severity of decompensation and systemic inflammation, and the presence of additional factors that may impair platelet function, such as acute kidney injury and bacterial infections. Although there are multiple, complex alterations of platelet function in cirrhosis, their net effect is not yet fully understood. More investigations evaluating the association between alterations of platelet function and bleeding/thrombosis may improve risk stratification in patients with decompensated cirrhosis. Besides hemostasis, the assessment of von Willebrand factor Ag and ADP-induced, whole-blood platelet aggregation normalized by platelet count (VITRO score and PLT ratio) are promising biomarkers to predict the risk of hepatic decompensation and survival in both compensated and decompensated patients. Further investigations into the in vivo interplay between platelets, circulating blood elements, and endothelial cells may help advance our understanding of cirrhotic coagulopathy. Here, we review the complex changes in platelets and primary hemostasis in cirrhosis and their potential clinical implications.

Cirrhotic patients have complex haemostatic abnormalities. Current evidence suggests stable cirrhotic (SC) patients have a "re-balanced" haemostatic state. However, limited data exists in acute decompensated (AD) or acute on chronic liver failure (ACLF) patients.We utilised thrombin generation analysis, fibrinolysis assessment, and evaluation of haemostatic parameters to assess haemostasis in liver disease of progressive severity.The study cohorts were comprised of: SC, n=8; AD n=44; ACLF, n=17; and Healthy Control (HC), n=35. There was a progressive increase across the cohorts in INR (p=0.0001), Factor VIII (p=0.0001) and VWF levels (p=0.0001) and a correspondingly decrease in anti-thrombin (p=0.0001), ADAMTS-13 (p=0.01) and fibrinogen levels (p=0.0001). In the presence of thrombomodulin, thrombin generation was equivalent or significantly higher in all the cohorts compared to HC (p=0.0001). Compared to AD, ACLF had a lower ETP (p=0.002) and thrombin peak (p=0.0001). There was no significant difference across the cohorts in clot lysis time (p=0.07), although compared to HC, AD had a significantly shorter lysis time (p=0.001).Our cohorts, despite significant differences in haemostatic parameters, displayed intact thrombin generation but progressive hypo-functional clot stability and potentially but not universal hyper-functional haemostasis.Copyright © 2017 Elsevier Inc. All rights reserved.

Thrombosis is a major cause of morbidity and mortality in cancer patients. Many clinical factors contribute to the high thrombotic risk of this condition, including the type of malignancy, its disease stage, anticancer therapies, and comorbidities. However, the cancer cell-specific prothrombotic properties together with the host cell inflammatory response are important players in the pathogenesis of the cancer-associated hypercoagulability. Tissue factor (TF) is the most important procoagulant protein expressed by cancer cells, and with other cancer tissue procoagulant properties highly contributes to the procoagulant phenotype of malignant cells. Recent discoveries indicate that oncogenes determine the procoagulant protein expression, including TF, in cancer tissues. In addition, in malignancy, TF is also overexpressed by host normal blood cells triggered by cancer-derived inflammatory stimuli. As a consequence, a subclinical activation of blood coagulation is typically present in cancer patients, as demonstrated by abnormalities of circulating thrombotic biomarkers. The relevance of measuring these biomarkers to determine the patient thrombotic risk level is under active investigation. The goal is to identify the high-risk subgroups to establish more accurate and targeted anticoagulation strategies to prevent thrombosis in cancer patients. Ultimately, the clarification of specific molecular mechanisms triggering blood coagulation in specific cancer types may also indicate alternative ways to inhibit clotting activation in these conditions. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin-antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One-hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm (range: 5-16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow-up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor-1 levels, independent of Model for End-Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper-coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression.© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. The intent is to evaluate the current data on mechanism of altered coagulation in patients with cirrhosis, provide guidance on the use of currently available testing of the coagulation cascade, and help practitioners use anticoagulation and pro-coagulants appropriately in patients with cirrhosis.This review is framed around the best practice points, which were derived from the most impactful publications in the area of coagulation in cirrhosis and agreed to by all authors. BEST PRACTICE ADVICE 1: Global tests of clot formation, such as rotational thromboelastometry, thromboelastography, sonorheometry, and thrombin generation, may eventually have a role in the evaluation of clotting in patients with cirrhosis, but currently lack validated target levels. BEST PRACTICE ADVICE 2: In general, clinicians should not routinely correct thrombocytopenia and coagulopathy before low-risk therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation in patients with hepatic synthetic dysfunction-induced coagulation abnormalities. BEST PRACTICE ADVICE 3: Blood products should be used sparingly because they increase portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-related acute lung injury, infection transmission, alloimmunization, and/or transfusion reactions. BEST PRACTICE ADVICE 4: The following transfusion thresholds for management of active bleeding or high-risk procedures may optimize clot formation in advanced liver disease: hematocrit ≥25%, platelet count >50,000, and fibrinogen >120 mg/dL. Commonly utilized thresholds for international normalized ratio correction are not supported by evidence. BEST PRACTICE ADVICE 5: Thrombopoietin agonists are a good alternative to platelet transfusion, but require time (about 10 days) to elevate platelet levels. BEST PRACTICE ADVICE 6: The large volume of fresh frozen plasma required to reach an arbitrary international normalized ratio target, limitations of the usual target, minimal effect on thrombin generation, and adverse effects on portal pressure limit the utility of this agent significantly. BEST PRACTICE ADVICE 7: The 4-factor prothrombin complex concentrate contains both pro- and anticoagulant factors that offer an attractive low-volume therapeutic to rebalance a disturbed hemostatic system. However, dosage is, in part, based on international normalized ratio, which is problematic in cirrhosis, and published experience in liver disease is limited. BEST PRACTICE ADVICE 8: Anti-fibrinolytic therapy may be considered in patients with persistent bleeding from mucosal oozing or puncture wound bleeding consistent with impaired clot integrity. Both ε-aminocaproic acid and tranexamic acid inhibit clot dissolution. Neither is believed to generate a hypercoagulable state, although both may exacerbate pre-existing thrombi. BEST PRACTICE ADVICE 9: Desmopressin releases von Willebrand factor as its primary hemostatic mechanism. As this factor is usually elevated in cirrhosis, the agent lacks a sound evidence-based foundation, but may be useful in patients with concomitant renal failure. BEST PRACTICE ADVICE 10: Systemic heparin infusion is recommended for symptomatic deep vein thrombosis and portal and mesenteric vein thrombosis, but there are unresolved issues regarding monitoring with both the anti-Xa assay and the partial thromboplastin time due to cirrhosis-related antithrombin deficiency (heparin cofactor). BEST PRACTICE ADVICE 11: Treatment of incidental portal and mesenteric vein thrombosis depends on estimated impact on transplantation surgical complexity vs risks of bleeding and falls. Therapy with low-molecular-weight heparin, vitamin K antagonists, and direct-acting anticoagulants improve portal vein repermeation vs observation alone. BEST PRACTICE ADVICE 12: Direct-acting anticoagulants, such as the factor Xa and thrombin inhibitors, are relatively safe and effective in stable cirrhotic patients, but are in need of further study in patients with more advanced liver disease.Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

Impaired secretion of an essential blood coagulation factor fibrinogen leads to hepatic fibrinogen storage disease (HFSD), characterized by the presence of fibrinogen-positive inclusion bodies and hypofibrinogenemia. However, the molecular mechanisms underlying the biogenesis of fibrinogen in the endoplasmic reticulum (ER) remain unexplored. Here we uncover a key role of SEL1L-HRD1 complex of ER-associated degradation (ERAD) in the formation of aberrant inclusion bodies, and the biogenesis of nascent fibrinogen protein complex in hepatocytes. Acute or chronic deficiency of SEL1L-HRD1 ERAD in the hepatocytes leads to the formation of hepatocellular inclusion bodies. Proteomics studies followed by biochemical assays reveal fibrinogen as a major component of the inclusion bodies. Mechanistically, we show that the degradation of misfolded endogenous fibrinogen Aα, Bβ, and γ chains by SEL1L-HRD1 ERAD is indispensable for the formation of a functional fibrinogen complex in the ER. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD indeed degrades and thereby attenuates the pathogenicity of two disease-causing fibrinogen γ mutants. Together, this study demonstrates an essential role of SEL1L-HRD1 ERAD in fibrinogen biogenesis and provides insight into the pathogenesis of protein-misfolding diseases.© 2024. The Author(s).

Patients with liver disease acquire complex changes in their hemostatic system, which results in a fragile rebalanced status. The status of the fibrinolytic system is controversial, as is the role of fibrinolytic dysfunction in bleeding and thrombosis in patients with cirrhosis. Here, we aimed to determine fibrinolytic status and its relationship with outcome in acutely ill patients with cirrhosis.

Physiological hemostasis is a balance between pro- and anticoagulant pathways, and in sepsis, this equilibrium is disturbed, resulting in systemic thrombin generation, impaired anticoagulant activity, and suppression of fibrinolysis, a condition termed sepsis-induced coagulopathy (SIC). SIC is a common complication, being present in 24% of patients with sepsis and 66% of patients with septic shock, and is often associated with poor clinical outcomes and high mortality.1,2 Recent preclinical and clinical studies have generated new insights into the molecular pathogenesis of SIC. In this article, we analyze the complex pathophysiology of SIC with a focus on the role of procoagulant innate immune signaling in hemostatic activation--tissue factor production, thrombin generation, endotheliopathy, and impaired antithrombotic functions. We also review clinical presentations of SIC, the diagnostic scoring system and laboratory tests, the current standard of care, and clinical trials evaluating the efficacies of anticoagulant therapies.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.

Background/Objectives: Liver transplantation (LT) is often complicated by severe bleeding and coagulopathy. Viscoelastic testing (VET) offers real-time, bedside assessment of coagulation and may improve transfusion management compared to standard tests. This study evaluates the clinical impact of VET implementation during liver transplantation on bleeding, transfusion requirements, complications, and mortality in a single Eastern European tertiary transplant center. Methods: We conducted a single-center before-and-after study comparing patients undergoing LT before and after the implementation of VET. All procedures were performed by the same surgical and anesthetic team using a standardized protocol. Data were collected retrospectively for the Before VET group and prospectively for the After VET group. We compared transfusion requirements, bleeding, complications, and mortality. Results: A total of 59 patients were included, 22 in the After VET group and 37 in the Before VET group. VET implementation was associated with lower intraoperative blood loss (median 4000 mL vs. 6000 mL, p = 0.017) and reduced red blood cell (RBC) transfusion volume (670 mL vs. 1000 mL, p = 0.008). FFP (0.23 vs. 1.59 units, p = 0.007) and platelet use (0.68 vs. 1.81 units, p = 0.035) were also significantly lower in the VET group, while fibrinogen use was higher (3.00 g vs. 2.00 g, p = 0.036). No differences were observed in complication rates or mortality at 30 days and 1 year in this small before-and-after study. Conclusions: VET improved transfusion precision and individualized coagulation management during LT, leading to reduced use of blood products. These findings support the adoption of VET as a standard of care in LT protocols, as it may enhance patient safety, even though no differences in postoperative complications or mortality were observed.

Background: Fresh frozen plasma (FFP) transfusions have been the mainstay of hemostatic intervention for the treatment of bleeding and coagulation abnormalities arising during liver transplantation (LT) for decades. However, numerous clinical studies showed that FFP has many side effects, including the risk of pathogen transmission, transfusion-associated circulatory overload (TACO), transfusion-related immunomodulation (TRIM), and transfusion-related acute lung injury (TRALI). These adverse events are particularly challenging in patients undergoing LT, who often suffer from severe portal hypertension, poor renal function and coexisting cardiac disease.The aims of this review are to summarize the pharmacological properties of currently available PCCs, to represent the theoretical benefits and the possible risks related to the use of these drugs in patients undergoing LT, and, finally, to review the current literature on the topic in order to highlight the evidence that currently supports PCC use in LT patients. Methods: The current literature on the topic was reviewed in order to highlight the evidence that currently supports PCC use in LT patients. Results: Prothrombin complex concentrates (PCCs) may offer several advantages when compared to FFP. Indeed, PCCs have been shown to reduce the risk of TACO, which during liver transplantation may deteriorate portal hypertension, increase intraoperative bleeding, and possibly reduce survival rates. One of the major concerns for PCC use is thrombogenicity. However, currently available PCCs are much safer as they contain inactivated forms of the vitamin K-dependent coagulation factors and protein C, protein S, antithrombin and/or heparin. Nowadays, the use of PCCs to correct coagulation abnormalities that occur during LT is an increasingly widespread practice. However, it is not yet clear what level of evidence supports this practice, and what the risks associated with it are. Conclusions: Administration of PCC in LT patients to correct haemostatic abnormalities seems to be well-tolerated, but the relationship between PCC use and thromboembolic events in the postoperative period remains unclear. Adequately powered, methodologically sound trials are urgently required for more definitive conclusions about the efficacy and safety of PCCs in a broad phenotype of LT recipients.