The thrombin generation assay (TGA), originally developed by McFarlane and Biggs in 1956, was modified in the 2000s by Hemker and coworkers. TGA aims to monitor the continuous generation of thrombin upon activation of coagulation in plasma by the addition of such triggers as small amounts of tissue factor, synthetic phospholipids, and calcium chloride. TGA is sensitive to hypo- and hypercoagulability and is affected by prohemostatic as well as antithrombotic drugs. The review of the current literature shows that TGA is mainly used to investigate conditions characterized by hypo- as well as hypercoagulability and as a laboratory tool to elucidate coagulation mechanisms that are not yet completely understood. This article aims to overview the value and limits of current procedures for TGA for the investigation of hemostasis.

Patients undergoing liver transplantation infrequently require extracorporeal membrane oxygenation (ECMO) support. However, when ECMO is required in the peritransplant period, several key considerations are required to maximize the efficacy of its support and minimize the risks of complications. This review seeks to briefly summarize the existing data supporting the use of ECMO in liver transplant patients and offers expert technical and practical advice from the authors' high-volume liver transplant center and ECMO program.

Although post-procedural bleedings are infrequent in patients with cirrhosis, they are associated with significant morbidity and mortality. Therefore, predicting and preventing such bleedings is important. Established predictors of post-procedural bleeding include high-bleeding risk procedure, severe cirrhosis and high body mass index; prognostic value of anemia, acute kidney injury and bacterial infection is more uncertain. While prothrombin time and international normalized ratio do not predict post-procedural bleeding, some evidence suggests that platelet count, whole blood thrombin generation assay and viscoelastic tests may be helpful in this context. Prevention of postprocedural bleeding involves careful management of antithrombotic drugs during the periprocedural period. Patients with cirrhosis present unique challenges due to altered pharmacokinetics and pharmacodynamics of antithrombotic drugs, but there is a lack of dedicated studies specifically focused on this patient population. Guidelines for periprocedural management of antithrombotic drugs developed for patients without liver disease are thus applied to those with cirrhosis. Some technical aspects may decrease the risk of post-procedural bleeding, namely ultrasoundguidance, opting for transjugular route rather than percutaneous route, and the level of expertise of the operator. The effectiveness of platelet transfusions or thrombopoietin-receptor agonists remains uncertain. Transfusion of fresh-frozen plasma, of fibrinogen, and administration of tranexamic acid are not recommended for reducing post-procedural bleeding in patients with cirrhosis. In conclusion, prediction of post-procedural requires a global approach taking into account the patients characteristics, the risk of the procedure, and the platelet count. There is little data to support prophylactic correction of hemostasis, and dedicated studies are needed.

(1) Background: Cirrhosis is associated with frequent alterations in standard coagulation tests that do not adequately reflect hemostasis. Thromboelastography provides a global assessment of coagulation and evaluates the functional status of clotting factors, fibrinogen, platelets, and fibrinolysis. The study aimed to assess whether liver disease severity leads to progressive alterations in the thromboelastography-based assessment of coagulation. (2) Methods: Consecutive patients with cirrhosis and abnormal standard coagulation tests (at least one of International Normalized Ratio > 2, platelet count < 50 × 103/µL, fibrinogen < 200 mg/dL) were analyzed using native thromboelastography. (3) Results: A total of 106 patients were included, of whom 69 (65.1%) had a normal thromboelastography. While the standard coagulation tests were significantly worse in patients in the Child C group (n = 62, 58.5%) than in patients staged in Child A and B, no significant differences existed between any of the thromboelastography variables. Of the 50 patients (47.1%) with an International Normalized Ratio > 2, only two patients (4%) had features of hypocoagulation, while 26% had features of hypercoagulability on thromboelastography. Patients with a platelet count < 50 × 103/µL had significantly lower platelet function as assessed by thromboelastography, yet only eight patients (20%) met the criteria for platelet transfusion. A thromboelastography-based transfusion protocol might lead to a 94.6% reduction in blood product transfusion indications in a simulation where the included patients would require interventional procedures. (4) Conclusion: Standard coagulation tests showed a poor correlation with thromboelastography. Based on thromboelastography, patients with severe, decompensated liver disease have a preserved hemostasis balance despite abnormal standard coagulation tests. Therefore, standard coagulation tests should not be used to guide the administration of blood products in patients with cirrhosis.

To determine the rate of platelet transfusion in patients with cirrhosis and severe thrombocytopenia (platelet counts <50 × 109/L) undergoing high-risk invasive procedures when prescribed by thromboelastography (TEG) compared with empirical and on-demand transfusion strategies.

This was a single-center, single-blinded, randomized controlled trial. Patients with cirrhosis and severe thrombocytopenia undergoing high-risk invasive procedures were randomized into 3 groups: TEG group, transfusions based on TEG parameters; standard of care (SOC) group, 3 units of random donor platelets before procedure; and on-demand group, transfusions based on procedural adverse events/clinician's discretion. The primary outcome was periprocedural platelet transfusion in each arm.

Eighty-seven patients were randomized (29 in each group) with no significant differences in demographics/coagulation profile/procedures. The median platelet count was 33 × 109/L (interquartile range, 26-43 × 109/L). Percutaneous liver biopsy was the most common procedure (46, 52.9%). Significantly lower number of patients in the TEG group received platelets (4 cases, 13.8%; 95% CI, 3.9-31.7) compared with SOC group (100%; 95% CI, 88.1-100; P < .001). Four patients in the on-demand group received platelets (13.8%; 95% CI, 3.9-31.7). Minor (World Health Organization [WHO] Grade 2) procedure-related bleeding occurred in 3 (10%; 95% CI, 2.2-27.4) patients in the TEG-guided transfusion group compared with 1 (3.4%; 95% CI, 0.1-17.8) patient each in the SOC and on-demand groups (P = .43), although the study was not powered for comparison of bleeding rates. No bleeding-related mortality was observed in any of the 3 groups.

TEG-prescribed transfusion reduced prophylactic transfusions in patients with cirrhosis and severe thrombocytopenia undergoing high-risk invasive procedures. The study was not powered for comparison of bleeding rates.

Thromboelastography (TEG) provides a global assessment of haemostasis and is potentially applicable to liver disease. The present study aimed to explore the utility of TEG for the evaluation of patients with chronic viral liver disease, which has previously not been investigated.

Demographic characteristics and TEG parameters were collected before surgery. Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores were used to categorise stages of liver cirrhosis. Liver resections were classified as low, medium and high complexity.

A total of 344 patients were included. Results showed significantly longer K-time, smaller α-angle and lower maximum amplitude (MA) with increasing liver disease severity as measured by the CTP and MELD scores ( P < 0.05 for all). After multivariable adjustment (including age, sex, liver disease aetiology, alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin, total bilirubin, haemoglobin and platelet count), TEG parameters (except R-times) were either weakly or inversely related to the severity of liver disease as defined by the MELD score (absolute r < 0.2 and P < 0.05 for all except R-times). R-times obtained before surgery were weakly correlated with perioperative blood loss ( r < 0.2 and P < 0.05 for all).

The correlation between TEG parameters and severity of liver disease was weak. In addition, R-times obtained before liver resection were weakly associated with perioperative blood loss after multivariable adjustments. TEG utility for haemostasis assessment and prediction of blood loss during liver resection should be further explored in high-quality studies.

Viscoelastic testing is increasingly being used in clinical and research settings to assess hemostasis. Indeed, there are potential situations in which viscoelastic testing is reportedly superior to standard routine laboratory testing for hemostasis. We report the current testing platforms and terminology, as well as providing a concise narrative review of the published evidence to guide its use in various clinical settings. Notably, there is increasing evidence of the potential utility of viscoelastic testing for assessment of direct oral anticoagulants, and bleeding associated with chronic liver disease, orthotopic liver transplantation, cardiac surgery, trauma, obstetrics and pediatrics.

Individuals with cirrhosis experience higher morbidity and mortality rates than the general population, irrespective of the type or scope of surgery. This increased risk is attributed to adverse effects of liver disease, encompassing coagulation dysfunction, altered metabolism of anesthesia and sedatives, immunologic dysfunction, hemorrhage related to varices, malnutrition and frailty, impaired wound healing, as well as diminished portal blood flow, overall hepatic circulation, and hepatic oxygen supply during surgical procedures. Therefore, a frequent clinical dilemma is whether surgical interventions should be pursued in patients with cirrhosis. Several risk scores are widely used to aid in the decision-making process, each with specific advantages and limitations. This review aims to discuss the preoperative risk factors in patients with cirrhosis, describe and compare surgical risk assessment models used in everyday practice, provide insights into the surgical risk according to the type of surgery and present recommendations for optimizing those with cirrhosis for surgical procedures. As the primary focus is on currently available risk models, the review describes the predictive value of each model, highlighting its specific advantages and limitations. Furthermore, for models that do not account for the type of surgical procedure to be performed, the review suggests incorporating both patient-related and surgery-related risks into the decision-making process. Finally, we provide an algorithm for the preoperative assessment of patients with cirrhosis before elective surgery as well as guidance perioperative management.

Non-variceal hemorrhage in patients with chronic liver disease (CLD) increases morbidity, mortality, and healthcare costs. There are limited data on risk factors for non-variceal hemorrhage in the CLD population. The aim of this study was to assess the predictive value of various clinical and laboratory parameters for non-variceal hemorrhage in CLD patients.

We conducted a retrospective cohort study of US veterans diagnosed with CLD between 2002 and 2018 within the Veterans Health Administration database. We derived candidate variables from existing risk prediction models for hemorrhage, risk calculators for severity of liver disease, Charlson index of prognostic comorbidities, and prior literature. We used a competing risk analysis to study the relationship between putative risk factors and incidence of non-variceal hemorrhage in patients with CLD.

Of 15,183 CLD patients with no history of cancer or anticoagulation use, 674 experienced non-variceal hemorrhage within 1 year of CLD diagnosis. In multivariable analysis, 11 of the 26 candidate variables independently predicted non-variceal hemorrhage: race, international normalized ratio (INR) > 1.5, bilirubin ≥ 2 mg/dL, albumin ≤ 3.5 g/dL, anemia, alcohol abuse, antiplatelet therapy, chronic kidney disease, dementia, proton pump inhibitor prescription, and recent infection.

In this study of almost 15,000 veterans, risk factors for non-variceal bleeding within the first year after diagnosis of CLD included non-Caucasian race, laboratory parameters indicating severe liver disease and recent infection in addition to the risk factors for bleeding observed in a general non-CLD population.

Cirrhosis presents with thrombocytopenia and possibly thrombocytopathy. Previous studies exploring platelet function gave conflicting results and most controversies are explained by the variety of methods employed for investigation. We sought to assess in-vitro the overall platelet function in cirrhosis. We investigated 34 patients by using the following tests. (i)Aggregometry. (ii)Measurement of the content of platelet granules. (iii)Cytometric platelet activation. (iv)Plasmatic markers of in-vivo platelet activation. (v)Platelet procoagulant activity by thrombin generation (TG) in platelet-rich plasma (PRP). TG measured in PRP for patients and controls was similar. Platelets from patients with cirrhosis showed reduction of aggregation and secretion of ATP. Similar results were observed for platelet activation parameters such as P-selectin expression and PAC-1 platelet binding. Plasma levels of βeta-thromboglobulin and soluble P-selectin, were increased in patients-vs-controls. In contrast, there were no patients-vs-controls differences for plasmatic platelet-factor-4. Results are consistent with a state of in-vivo platelet activation and decreased in-vitro aggregation. Since bleeding events following invasive procedures are uncommon in cirrhosis, we speculate that in-vitro aggregometry testing does not reflect the situation occurring in-vivo. Results of the study and pathophysiological considerations support the conclusion that platelet function in cirrhosis as determined by aggregometry, although somewhat impaired, may support the overall hemostatic potential, which is needed for most invasive interventions. These conclusions are in line with the recommendations of international guidelines, warning against indiscriminate use of prophylactic preprocedural administration of platelets before invasive procedures. Decision on platelet support should not be made based on in-vitro laboratory testing for platelet function.

Patients with cirrhosis have a normal to increased thrombin generation (TG) capacity in platelet-poor plasma (PPP). By reflecting the contribution of all circulating blood cells, whole blood (WB) TG may allow a more physiological assessment of coagulation.

We compared WB-TG vs PPP-TG in patients with cirrhosis.

Assessment of coagulation included routine tests, factor VIII, natural anticoagulants, PPP-TG, and WB-TG. TG assays were performed with and without thrombomodulin. Twenty-five healthy subjects were included as controls.

We included 108 patients (Child-Pugh A/B/C, 44/24/40). Compared with controls, patients had significantly lower platelet count, longer international normalized ratio, higher FVIII, and lower levels of protein C/S and antithrombin. Regarding thrombomodulin-modified TG assays, in compensated cirrhosis, both PPP-TG and WB-TG indicated an increased TG capacity, as reflected by an endogenous thrombin potential (ETP) significantly higher than controls. In contrast, in decompensated cirrhosis, PPP-TG indicated a hypercoagulable state with increased ETP, higher peak height, and shorter time-to-peak than controls, whereas WB-TG revealed a progressive impairment of TG kinetics and total capacity, ultimately resulting in a profound hypocoagulable state in patients with Child-Pugh C cirrhosis (ie, significant prolongation of lag time and time-to-peak with reduction of both ETP and peak height). In decompensated patients, bacterial infections and severity of anemia were associated with a further reduction of both ETP and peak height.

Compensated cirrhosis is associated with an increased TG capacity. In decompensated cirrhosis, contrary to PPP-TG, which indicates hypercoagulability, WB-TG shows a significant hypocoagulable state. The clinical value of these findings deserves further investigation.

New global laboratory procedures mimicking the in vivo hemostasis process led to the changing paradigm of cirrhosis from the prototype of hemorrhagic diseases to a condition in which hemostasis is normal but fragile, thus justifying the hemorrhagic/thrombotic tendencies that affect these patients. The new paradigm was instrumental to change the management of cirrhosis. For example, international guidelines warn against the entrenched practice of testing patients with conventional hemostasis tests and infusing those with abnormalities with fresh-frozen plasma, coagulation factor concentrates, or platelets, prior to surgery/invasive procedures. These recommendations are, however, largely disattended. The practice of testing patients with the prothrombin time or viscoelastometry and using arbitrary cutoffs to make decisions on perioperative prophylaxis is still common and probably driven by medicolegal issues. There is no doubt that prothrombin time and congeners tests are unable to predict bleeding in cirrhosis. However, it cannot be excluded that some tests may be useful in patients who are severely decompensated. Large prospective collaborative studies are warranted. Enrolled patients should be randomized to receive perioperative prophylaxis based on laboratory testing (eg, viscoelastometry, thrombomodulin-modified thrombin generation) or to usual care. However, for these trials to be useful, a third group of patients who do not receive prophylaxis should be included. In conclusion, until results from these studies are available, physicians attending cirrhosis should refrain from using laboratory tests with arbitrary cutoffs to make decision on perioperative prophylaxis. Decision should be made by considering the clinical history of individual patients and the risk of hemorrhage of specific procedures.

Coagulation management in the patient with cirrhosis has undergone a significant transformation since the beginning of this century, with the concept of a rebalancing between procoagulant and anticoagulant factors. The paradigm that patients with cirrhosis have a greater bleeding tendency has changed, as a result of this rebalancing. In addition, it has brought to light the presence of complications related to thrombotic events in this group of patients. These guidelines detail aspects related to pathophysiologic mechanisms that intervene in the maintenance of hemostasis in the patient with cirrhosis, the relevance of portal hypertension, mechanical factors for the development of bleeding, modifications in the hepatic synthesis of coagulation factors, and the changes in the reticuloendothelial system in acute hepatic decompensation and acute-on-chronic liver failure. They address new aspects related to the hemorrhagic complications in patients with cirrhosis, considering the risk for bleeding during diagnostic or therapeutic procedures, as well as the usefulness of different tools for diagnosing coagulation and recommendations on the pharmacologic treatment and blood-product transfusion in the context of hemorrhage. These guidelines also update the knowledge regarding hypercoagulability in the patient with cirrhosis, as well as the efficacy and safety of treatment with the different anticoagulation regimens. Lastly, they provide recommendations on coagulation management in the context of acute-on-chronic liver failure, acute liver decompensation, and specific aspects related to the patient undergoing liver transplantation.

Patients with advanced liver diseases frequently acquire profound alterations in their hemostatic system. Simultaneous changes in procoagulant and anticoagulant systems result in a reset in the hemostatic balance with a relatively neutral net effect, although there are notable hypocoagulable and hypercoagulable features in the hemostatic system in patients with liver disease. Laboratory and clinical studies have demonstrated that patients have a relatively well-preserved hemostatic system even though routine diagnostic tests of hemostasis (prothrombin time, platelet count) suggest a bleeding tendency. Routine diagnostic tests of hemostasis are unsuitable to assess the hemostatic status of patients with liver disease, as these tests are insensitive for the concurrent prohemostatic and antihemostatic changes in these patients. These tests are, however, frequently requested in patients with liver disease, as they are well established indicators of severity of liver disease. This paper will discuss commonly used diagnostic and research-type hemostatic tests and will outline how test results should be interpreted in patients with liver disease.

Thromboelastography (TEG) informs the need for blood product transfusions to prevent procedural bleeding complications in patients with cirrhosis. We aimed to evaluate the impact of using a TEG-based transfusion protocol on blood product utilization before paracentesis and the post-paracentesis hemoperitoneum (PPH) incidence.

We conducted an ambispective analysis of patients with cirrhosis who underwent paracentesis from 2017 to 2021. In May 2019, we enacted a TEG-based transfusion protocol to guide pre-paracentesis blood product use. Patients with platelets < 20,000 or international normalized ratio ≥ 4 underwent TEG and received blood products if r value > 10 min or MA <30 mm. Patients were divided into pre-TEG and post-TEG protocol cohorts based on the date of paracentesis. Pre-paracentesis blood product transfusions in the form of platelets, fresh frozen plasma, and cryoprecipitates were recorded. PPH was defined as a decrease in hemoglobin of ≥1 g and the presence of blood on diagnostic imaging and/or the need for therapeutic intervention.

A total of 483 patients underwent 1281 paracenteses. The main etiologies of cirrhosis were alcohol (43%) and NASH (25%), and the mean MELD-sodium was 22±6. Pre-TEG and post-TEG protocol cohort sizes were similar: 253 patients and 607 paracenteses versus 230 patients and 674 paracenteses. After TEG-protocol implementation, blood product transfusions decreased significantly (228 vs. 49 products, p<0.001) with associated cost savings. One patient in each cohort developed PPH.

Implementation of a pre-paracentesis TEG-based transfusion protocol for patients with cirrhosis successfully resulted in decreased blood product use with no associated increase in incidence of PPH.

Excessive bleeding is relatively common in adult inpatients, whether as the primary reason for admission or as a development during the hospital stay. Common causes include structural issues, medication effects, and systemic illnesses; occasionally, unexpected bleeding can develop as a result of an undiagnosed or newly acquired bleeding disorder. The first step in caring for the inpatient who is bleeding is to determine whether the bleeding symptom is truly new or whether the patient has a history of abnormal bleeding. Patients with a history of abnormal bleeding may warrant evaluation for inherited bleeding disorders, such as platelet function disorders, von Willebrand disease, hemophilia, or rare factor deficiencies. Patients with no history of bleeding, for whom other causes, such as liver dysfunction, medication effect, disseminated intravascular coagulation, or certain vitamin deficiencies have been ruled out may require evaluation for acquired coagulopathies, such as acquired hemophilia or acquired von Willebrand disease. Here, we present 3 cases to discuss the diagnosis and management of the 2 most common acquired bleeding disorders as well as a patient with a congenital bleeding disorder with a historical diagnosis.

Thromboelastography (TEG) is a laboratory assay utilized to evaluate hemostatic properties of blood, identify coagulopathy, and guide blood product administration. While the clinical use of TEG started in the care of surgical patients, the assay has now been incorporated more routinely in the care of the medical patient as well. In this review, we explore the evolution of TEG from the historical perspective of its inception to the current state of the art of the assay. The TEG procedure and its measurements are illustrated along with a table that summarizes recommendations from across the medical and surgical literature. After each section, we review salient learning points to provide the busy clinician with information that can be immediately integrated at the bedside. We conclude with a series of summary questions to check for comprehension and direct the reader to additional resources to improve their knowledge of TEG.

Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non-portal hypertensive-related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration.

Concepts regarding the status of the coagulation process in cirrhosis are rapidly changing. Instead of a disease defined by excessive bleeding risk, recent studies have shown cirrhosis to be associated with a fragile state of rebalanced hemostasis, easily swayed in either direction, thrombosis, or bleeding. These findings, combined with the ever-growing population of patients with cirrhosis with an indication for anticoagulation (AC) and the emergence of the non-alcoholic fatty liver disease epidemic, have prompted a reexamination of the use of AC in patients with cirrhosis, either as a treatment for a concurrent thrombotic disorder or even as a possible therapeutic option that could influence the natural course of the disease and its complications. In recent years, a significant number of studies have been formulated to evaluate these possibilities. These studies evaluated, among others, the efficacy and safety of AC in thrombotic disorders or thrombotic complications of cirrhosis, its effect on survival, and the class of anticoagulants which is more suitable for patients with cirrhosis, depending on disease severity. This review examines recent studies investigating the use of AC in patients with cirrhosis and attempts to provide a simple guide for clinicians regarding the use of AC in patients with cirrhosis and its potential risks and benefits.

Cirrhotic patients with severe thrombocytopenia are at increased risk of bleeding during invasive procedures. The need for preprocedural prophylaxis aimed at reducing the risk of bleeding in cirrhotic patients with thrombocytopenia who undergo scheduled procedures is assessed via the platelet count; however, establishing a minimum threshold considered safe is challenging. A platelet count ≥ 50000/μL is a frequent target, but levels vary by provider, procedure, and specific patient. Over the years, this value has changed several times according to the different guidelines proposed in the literature. According to the latest guidelines, many procedures can be performed at any level of platelet count, which should not necessarily be checked before the procedure. In this review, we aim to investigate and describe how the guidelines have evolved in recent years in the evaluation of the minimum platelet count threshold required to perform different invasive procedures, according to their bleeding risk.

Patients with cirrhosis frequently require admission to the intensive care unit as complications arise in the course of their disease. These admissions are associated with high short- and long-term morbidity and mortality. Thus, understanding and characterizing complications and unique needs of patients with cirrhosis and acute-on-chronic liver failure helps providers identify appropriate level of care and evidence-based treatments. While there is no widely accepted critical care admission criteria for patients with cirrhosis, the presence of organ failure and primary or nosocomial infections are associated with particularly high in-hospital mortality. Optimal management of patients with cirrhosis in the critical care setting requires a system-based approach that acknowledges deviations from canonical pathophysiology. In this review, we discuss appropriate considerations and evidence-based practices for the general care of patients with cirrhosis and critical illness.

Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.

Background and Objectives: The risk of bleeding after endoscopic procedures in patients with liver cirrhosis remains unclear because of secondary blood coagulation disorders. In this study, we used various indices to evaluate the risk of bleeding in patients with cirrhosis. Materials and Methods: Patients with liver cirrhosis aged ≥18 years who underwent endoscopic interventions at Kyung Hee University Hospital at Gangdong between February 2007 and September 2021 were included. Clinical information, including demographic data, laboratory results, the presence of cirrhosis complications, and the degree of fibrosis, was checked and evaluated based on medical records. Results: A total of 101 patients with cirrhosis were analyzed. A total of 16 of the 101 patients (15.8%) experienced bleeding after the endoscopic procedure. One patient (0.99%) presented with spurting, while the others presented with mild oozing. All patients underwent hemostatic procedures using hemoclips. The presence of a varix significantly increased post-endoscopic bleeding (p = 0.03). Patients with FIB > 3.25 showed a statistically significant bleeding tendency (p = 0.00). Conclusions: There was no significant difference in bleeding risk according to the platelet count, prothrombin time, Child−Pugh score, and model for end-stage liver disease (MELD). Considering the degree of liver fibrosis and the invasiveness of the planned procedure, most endoscopic procedures can be performed safely but should be further evaluated in a cohort with a larger sample size.

Thromboelastometry is considered the best method to assesses hemostasis in liver disease. Diagnostic performance could be improved by adding protein C activators such as thrombomodulin or Protac®. We assessed changes in ROTEM parameters after the addition of Protac® in patients with acute-on-chronic liver failure (ACLF), acute decompensation (AD), and healthy individuals (HI) to define different hemostasis patterns, considering standard and velocity ROTEM parameters, and assess whether Protac® can improve the definition of the pattern.

Pre-test, we investigated whether diluted EXTEM reagent improved the effect of Protac® on the clotting time (CT)-ratio with and without Protac®. Ten ACLF and 20 AD patients and 21 HI were included in the main study.

Standard EXTEM was used in the main study. INTEM CFT, INTEM A5 (inverse), and INTEM TPI (inverse) were the parameters that best differentiated liver disease from HI (ROC AUC, 0.921, 0.906, and 0.928, respectively; all P-values < 0.001). Combining INTEM CFT with EXTEM LI60-ratio only slightly improved the diagnostic performance (ROC AUC, 0.948; P < 0.001). EXTEM LI60 and INTEM maxV-t were the parameters that best differentiated between ACLF and AD patients (ROC AUC, 0.743, P = 0.033; and 0.723, P = 0.050; respectively). Combining EXTEM LI60 + INTEM maxV-t moderately improved the diagnostic performance (ROC AUC, 0.81, P < 0.001).

ROTEM velocity, fibrinolysis parameters and the indices calculated improve the diagnosis in combination with standard parameters (e.g., CFT and A5). Ratios calculated with and without Protac® (e.g., EXTEM LI60-ratio) only slightly increased the diagnostic performance in discriminating hemostasis patterns.

Abnormal bleeding in patients with liver disease may result from elevated portal pressure and varix formation, reduced hepatic synthesis of coagulation proteins, qualitative platelet dysfunction, and/or thrombocytopenia. Major mechanisms of thrombocytopenia in liver disease include splenic sequestration and impaired platelet production due to reduced thrombopoietin production. Alcohol and certain viruses may induce marrow suppression. Immune thrombocytopenia (ITP) may co-occur in patients with liver disease, particularly those with autoimmune liver disease or chronic hepatitis C. Drugs used for the treatment of liver disease or its complications, such as interferon, immunosuppressants, and antibiotics, may cause thrombocytopenia. Periprocedural management of thrombocytopenia of liver disease depends on both individual patient characteristics and the bleeding risk of the procedure. Patients with a platelet count higher than or equal to 50 000/µL and those requiring low-risk procedures rarely require platelet-directed therapy. For those with a platelet count below 50 000/µL who require a high-risk procedure, platelet-directed therapy should be considered, especially if the patient has other risk factors for bleeding, such as abnormal bleeding with past hemostatic challenges. We often target a platelet count higher than or equal to 50 000/µL in such patients. If the procedure is elective, we prefer treatment with a thrombopoietin receptor agonist; if it is urgent, we use platelet transfusion. In high-risk patients who have an inadequate response to or are otherwise unable to receive these therapies, other strategies may be considered, such as a trial of empiric ITP therapy, spleen-directed therapy, or transjugular intrahepatic portosystemic shunt placement.

Platelet transfusion in acute variceal bleeding (AVB) is recommended by few guidelines and is common in routine clinical practice, even though the effect of thrombocytopenia and platelet transfusion on the outcomes of AVB is unclear.

To determine how platelet counts, platelets transfusions, and fresh frozen plasma transfusions affect the outcomes of AVB in cirrhosis patients in terms of bleeding control, rebleeding, and mortality.

Prospectively maintained database was used to analyze the outcomes of cirrhosis patients who presented with AVB. The outcomes were assessed as the risk of rebleeding at days 5 and 42, and risk of death at day 42, considering the platelet counts and platelet transfusion. Propensity score matching (PSM) was used to compare the outcomes in those who received platelet transfusion. Statistical comparisons were done using Kaplan-Meier curves with log-rank tests and Cox-proportional hazard model for rebleeding and for 42-d mortality.

The study included 913 patients, with 83.5% men, median age 45 years, and Model for End-stage Liver Disease score 14.7. Platelet count < 20 × 109/L, 20-50 × 109/L, and > 50 × 109/L were found in 23 (2.5%), 168 (18.4%), and 722 (79.1%) patients, respectively. Rebleeding rates were similar between the three platelet groups on days 5 and 42 (13%, 6.5%, and 4.7%, respectively, on days 5, P = 0.150; and 21.7%, 17.3%, and 14.4%, respectively, on days 42, P = 0.433). At day 42, the mortality rates for the three platelet groups were also similar (13.0%, 23.2%, and 17.2%, respectively, P = 0.153). On PSM analysis patients receiving platelets transfusions (n = 89) had significantly higher rebleeding rates on day 5 (14.6% vs 4.5%; P = 0.039) and day 42 (32.6% vs 15.7%; P = 0.014), compared to those who didn't. The mortality rates were also higher among patients receiving platelets (25.8% vs 23.6%; P = 0.862), although the difference was not significant. On multivariate analysis, platelet transfusion and not platelet count, was independently associated with 42-d rebleeding. Hepatic encephalopathy was independently associated with 42-d mortality.

Thrombocytopenia had no effect on rebleeding rates or mortality in cirrhosis patients with AVB; however, platelet transfusion increased rebleeding on days 5 and 42, with a higher but non-significant effect on mortality.

Patients with chronic liver disease (CLD) often present with an elevated international normalized ratio (INR). Although elevated INR reflects a higher risk of hemorrhage among warfarin users, its clinical significance in CLD patients is less clear.

We used Veterans Health Administration data to quantify the association between INR and (non-variceal) hemorrhage in patients with CLD compared to warfarin users.

We performed a multivariate competing risk analysis to study the association between INR and hemorrhage in the two cohorts. We used an interaction term between INR and cohort (CLD/warfarin users) to test if INR had different effects on hemorrhage in the two cohorts.

Data from 80 134 patients (14, 412 with CLD and 65, 722 taking warfarin) were analyzed. The effect of INR on the risk of hemorrhage differed between CLD patients and warfarin users (interaction P < .001). As INR increased above 1.5, the adjusted hazard ratio (aHR) for hemorrhage in CLD patients increased to 2.25 but remained fairly constant with further elevation of INR values. In contrast, the risk of hemorrhage in patients taking warfarin remained low with INR in the subtherapeutic (INR <2.0) and therapeutic ranges (INR 2.0-3.0), and increased exponentially with INR in the supratherapeutic range (aHR 1.64 with INR >3.0-3.5, and 4.70 with INR >3.5).

The relationship between INR and risk of hemorrhage in CLD patients is different from that in warfarin users. Caution should be exercised extrapolating data from warfarin users to make clinical decisions in CLD patients.

The prevention and management of bleeding and thrombosis in patients with cirrhosis poses several difficult clinical questions. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics, including current views on haemostasis in liver disease, controversy regarding the need to correct thrombocytopenia and abnormalities in the coagulation system in patients undergoing invasive procedures, and the need for thromboprophylaxis in hospitalised patients with haemostatic abnormalities. Multiple recommendations in this document are based on interventions that the panel feels are not useful, even though widely applied in clinical practice.

Patients with hepatitis B-related cirrhosis complicated with thrombocytopenia have a higher risk of bleeding, which may lead to higher mortality. We aimed to explore the efficacy and safety of recombinant human thrombopoietin (rhTPO) in the treatment of hepatitis B-related cirrhosis complicated with severe thrombocytopenia. Patients with hepatitis B-related compensated liver cirrhosis complicated with severe thrombocytopenia were divided into four groups according to the treatment method for thrombocytopenia. Platelet counts, the appearance of bleeding symptoms and adverse events were evaluated during the observation period. Also during the observational period, the platelet counts in the prednisone group, rhTPO group and prednisone plus rhTPO group were higher than those in the no treatment group. Patients without splenomegaly reacted better to rhTPO. Fewer bleeding events of grade 2 or worse were observed in the three treatment groups compared to the no treatment group. The platelet counts at baseline and treatment with rhTPO and/or prednisone were factors associated with bleeding events of grade 2 or worse in multivariate analysis. There could be a potential advantage for the use of rhTPO plus prednisone based on higher platelet counts and fewer bleeding events. Treatment with rhTPO was more effective in patients without splenomegaly.

Prolonged prothrombin time and thrombocytopenia are common in patients with cirrhosis. These parameters do not reflect the overall hemostatic rebalance or bleeding risk in the periprocedural setting; however, attempts to correct these parameters remain frequent. We review the literature on periprocedural bleeding risk, bleeding risk factors, and the risk and benefits of hemostatic interventions in patients with cirrhosis. We provide guidance recommendations on evaluating bleeding risk in this patient group and management of hemostatic abnormalities in the periprocedural setting.

The combination of frequently abnormal hemostatic markers and catastrophic bleeding as seen with variceal hemorrhage has contributed to the longstanding misperception that chronic liver disease (CLD) constitutes a bleeding diathesis. Laboratory studies of hemostasis in liver disease consistently challenge this with global coagulation assays incorporating activation of the protein C pathway demonstrating rebalanced hemostasis. It is now recognized that bleeding in CLD is predominantly secondary to portal hypertension (rather than a coagulopathy) and additionally that these patients are at increased risk of venous thrombosis, particularly in the portal venous system. This narrative review describes the current understanding of hemostasis in liver disease, as well as the periprocedural management of hemostasis and anticoagulation for management of venous thromboembolism in patients with CLD.

Severe thrombocytopenia in cirrhosis can preclude invasive procedures. Platelet transfusion is recommended if platelet count pre-procedure is potential alternative to platelet transfusion is thrombopoietin-receptor (TPO) agonists.

Evaluate TPO-agonist efficacy and safety in cirrhotic patients with severe thrombocytopenia undergoing invasive procedures.

Randomized control trials (RCT) from electronic reference databases were searched from inception till December 2019. PRISMA guidelines were followed. Primary outcome was platelet transfusion avoidance. Secondary outcomes were weighted mean difference (WMD) in platelet count from baseline to pre-procedure and rates of major adverse events (AE). Pooled Odds Ratio (OR) were estimated using a random-effects model.

Six RCTs with 1,229 patients were included. All studies had low risk of bias. Compared with placebo, those treated with TPO-agonists had a pooled OR of 0.12(0.08-0.17), P<0.01 for platelet transfusion avoidance, and WMD in platelet count (x10 3 /µL) of 35.6(28.6-42.7), P<0.01. Major AE did not differ between groups [Pooled OR: 0.87(0.47-1.62), P=0.66].

Compared to placebo, TPO-agonists used in cirrhotic patients with severe thrombocytopenia prior to elective invasive procedures had 88% reduced odds of requiring peri-procedural platelet transfusion and increased platelet count pre-procedure, with no difference in AE rates.

This study was concerned with whether vWF (von Willebrand factor) and a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) has altered in patients with cirrhosis and extrahepatic portal hypertension (EPH). We aimed to investigate changes to vWF and ADAMTS13 in children with cirrhosis and EPH.

This study was conducted between January and October 2019 with both cirrhosis and EPH patients and with healthy volunteers. The von Willebrand factor antigen (vWF:Ag), von Willebrand Ristocetin cofactor (vWF:RCo), and ADAMTS13 antigen and activity were studied.

Twenty-eight children with cirrhosis, 16 children with EPH, and 20 healthy controls were included in the study. vWF:Ag and vWF:RCo levels were higher in patients with cirrhosis than in healthy controls (171.65±101.67 vs. 85.86±30.58, P<0.01 and 121.62±55.83 vs. 61.52±27.03, P<0.01, respectively). vWF:Ag and vWF:RCo levels were higher in patients with EPH than in healthy controls (133.93±80.13 vs. 85.86±30.58, P<0.01 and 103.18±58.55 vs. 61.52±27.03, P=0.02, respectively). The ADAMTS13 antigen and activity levels were lower in patients with cirrhosis than in healthy controls (0.58±0.23 vs. 0.97±0.15, P<0.01 and 49.91±22.43 vs. 86.51±22.07, P=0.02, respectively). The ADAMTS13 antigen and activity levels were lower in patients with EPH than in healthy controls (0.69±0.11 vs. 0.97±0.15, P=0.03; and 68.50±13.29 vs. 86.51±22.07, P=0.02, respectively). The increase in vWF and the decrease in ADAMTS13 were more pronounced in cirrhotic patients with autoimmune hepatitis (AIH) than in non-AIH patients.

While levels of vWF:Ag and vWF:RCo increased in children with cirrhosis and EPH, levels of the ADAMTS13 antigen and ADAMTS13 activity decreased. These alterations were more pronounced in patients with AIH-derived cirrhosis.

Hepatic cirrhosis leads to numerous hematologic derangements resulting in a complex and tenuously rebalanced hemostatic milieu. The utility of common hematologic tests including the INR and aPTT in assessing hemostatic and thrombotic risk in patients with cirrhosis is limited, and consensus on transfusion thresholds and proper management of thrombotic complications continues to evolve. This review summarizes the pathophysiology of key derangements of hemostasis including those of platelets, von Willebrand factor, pro- and anticoagulation factors, and fibrin. Additionally, the pathogenesis, consequences, optimal management, and prevention of major thrombotic and bleeding complications in cirrhosis arte discussed.