Production of physiological amounts of hemostatic proteins by human donor livers during ex situ long-term normothermic machine perfusion for up to 7 days.

Background: Normothermic machine perfusion (NMP) is used for preservation and assessment of human donor livers prior to transplantation. During NMP, the liver is metabolically active, which allows detailed studies on the physiology of human livers.

Objectives: To study the production of hemostatic proteins in human donor livers during NMP for up to 7 days.

Patients with metabolic dysfunction-associated steatotic liver disease have preserved responses to antiplatelet drugs.

Background: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at a risk of developing cardiovascular disease. Antiplatelet therapy not only prevents cardiovascular disease in these patients, but may also lower the risk of progression into advanced stages of fibrosis. However, patients with MASLD-associated cirrhosis often have complex changes in the hemostatic system and have been excluded from randomized trials.

Coagulation factor XIII is a critical driver of liver regeneration after partial hepatectomy.

Background: Activation of coagulation and fibrin deposition in the regenerating liver appears to promote adequate liver regeneration in mice. In humans, perioperative hepatic fibrin deposition is reduced in patients who develop liver dysfunction after partial hepatectomy (PHx), but the mechanism underlying reduced fibrin deposition in these patients is unclear.

Methods And Results: Hepatic deposition of cross-linked (ie, stabilized) fibrin was evident in livers of mice after two-thirds PHx.

Von Willebrand factor is an independent predictor of short-term mortality in acutely ill patients with cirrhosis.

Background And Aims: Levels of von Willebrand factor (VWF) are elevated in patients with cirrhosis, and correlate well with disease severity. In patients with decompensated cirrhosis (DC), plasma VWF is associated with mortality. The value of VWF in predicting short-term mortality risk in patients with acute-on-chronic liver failure (ACLF) is, however, unclear.

Fibrin clots from patients with acute-on-chronic liver failure are weaker than those from healthy individuals and patients with sepsis without underlying liver disease.

Background: Previous studies identified decreased clot permeability, without differences in fibrin fiber density in clots, from patients with cirrhosis compared with those from healthy controls (HCs). Fibrinogen hypersialylation could be the reason for this discrepancy.

Objectives: The aim of this work was to study mechanical properties of clots and reassess clot permeability in relation to hypersialylation in patients with stable cirrhosis, acute decompensation, and acute-on-chronic liver failure (ACLF).

Normothermic Machine-perfused Human Donor Livers Produce Functional Hemostatic Proteins.

Background: Normothermic machine perfusion (NMP) is used for the viability assessment of high-risk donor livers before transplantation. The production of hemostatic proteins is one of the major synthetic functions of the liver. The objective of this study was to measure the concentration and functionality of hemostatic proteins concentration in the NMP perfusate of human donor livers.

The international normalised ratio to monitor coagulation factor production during normothermic machine perfusion of human donor livers.

Background: Normothermic machine perfusion (NMP) of donor livers allows for new diagnostic and therapeutic strategies. As the liver produces most of the haemostatic proteins, coagulation assays such as the International Normalised Ratio (INR) performed in perfusate may be useful to assess hepatocellular function of donor livers undergoing NMP. However, high concentrations of heparin and low levels of fibrinogen may affect coagulation assays.

In vivo generation of thrombin in patients with liver disease without apparent evidence of activation of the intrinsic or extrinsic pathway of coagulation.

Background: Patients with liver diseases are in a hypercoagulable state, as evidenced by enhanced in vitro thrombin generating capacity and elevated plasma levels of markers of in vivo thrombin generation. However, it is unknown by which mechanism in vivo activation of coagulation occurs.

Objectives: We aimed to clarify the mechanisms underlying enhanced in vivo thrombin generation to provide a rationale for targeted anticoagulant therapy.

Clinically relevant increases in the international normalized ratio and model of end-stage liver disease score by therapeutic doses of direct oral anticoagulants in patients with cirrhosis.

Background: Patients with cirrhosis are increasingly using direct oral anticoagulants (DOACs) in therapeutic doses for the treatment of portal vein thrombosis or for concomitant atrial fibrillation. DOACs may affect routine diagnostic tests of coagulation including the international normalized ratio (INR). The INR is a part of the model of end-stage liver disease (MELD) score, a validated score that predicts the mortality risk in patients with cirrhosis and is used to prioritize patients for liver transplantation.

The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study.

Background: A hypercoagulable state is not associated with development of portal vein thrombosis in cirrhosis, as we previously demonstrated. However, some groups demonstrated elevated levels of inflammatory markers and activation of hemostasis in the portal vein (PV) compared to posthepatic veins, but because the liver is involved in clearance of these markers, we hypothesize that interpretation of these data is not straightforward.

Aim: To determine whether the PV has particular proinflammatory/hypercoagulable characteristics by comparing plasma sampled in the PV, hepatic vein (HV), and the systemic circulation.

Fibrin clot quality in acutely ill cirrhosis patients: Relation with outcome and improvement with coagulation factor concentrates.

Background & Aims: Patients with liver disease may acquire substantial changes in their hemostatic system, which are most pronounced in patients who are critically ill. Changes in the quality of the fibrin clot in critically ill patients have not been studied in detail. Here we assessed markers of fibrin clot quality and effects of coagulation factor concentrates in patients with acutely decompensated (AD) cirrhosis and acute on chronic liver failure (ACLF).

Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome.

Background And Aims: Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease.

Nonmalignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin-rich thrombus.

Background And Aim: Portal vein thrombosis (PVT) is a common complication of cirrhosis. The exact pathophysiology remains largely unknown, and treatment with anticoagulants does not lead to recanalization of the portal vein in all patients. A better insight into the structure and composition of portal vein thrombi may assist in developing strategies for the prevention and treatment of PVT.

Aggravation of fibrin deposition and microthrombus formation within the graft during kidney transplantation.

In kidney transplantation, microthrombi and fibrin deposition may lead to local perfusion disorders and subsequently poor initial graft function. Microthrombi are often regarded as donor-derived. However, the incidence, time of development, and potential difference between living donor kidneys (LDK) and deceased donor kidneys(DDK), remains unclear.

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor.

 Aprotinin is a broad-acting serine protease inhibitor that has been clinically used to prevent blood loss during major surgical procedures including cardiac surgery and liver transplantation. The prohemostatic properties of aprotinin likely are related to its antifibrinolytic effects, but other mechanisms including preservation of platelet function have been proposed.  Here we assessed effects of aprotinin on various hemostatic pathways in vitro, and compared effects to tranexamic acid(TXA), which is an antifibrinolytic but not a serine protease inhibitor.

Heparins have adequate ex vivo anticoagulant effects in hospitalized patients with cirrhosis.

Background: Patients with cirrhosis are at risk of venous thromboembolism (VTE), but strategies for thromboprophylaxis have not been defined. Previous in vitro studies suggest an altered anticoagulant effect of heparins in patients with cirrhosis.

Objectives: To assess the anticoagulant effects of prophylactic low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) doses in patients with cirrhosis in a real-life clinical setting.

Controlled DCD Liver Transplantation Is Not Associated With Increased Hyperfibrinolysis and Blood Loss After Graft Reperfusion.

Background: The specific effect of donation after circulatory death (DCD) liver grafts on fibrinolysis, blood loss, and transfusion requirements after graft reperfusion is not well known. The aim of this study was to determine whether transplantation of controlled DCD livers is associated with an elevated risk of hyperfibrinolysis, increased blood loss, and higher transfusion requirements upon graft reperfusion, compared with livers donated after brain death (DBD).

Methods: A retrospective single-center analysis of all adult recipients of primary liver transplantation between 2000 and 2019 was performed (total cohort n = 628).

Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality.

Background And Aims: Patients with severe coronavirus disease 2019 (COVID-19) are at significant risk of thrombotic complications. However, their prothrombotic state is incompletely understood. Therefore, we measured in vivo activation markers of hemostasis, plasma levels of hemostatic proteins, and functional assays of coagulation and fibrinolysis in plasma from patients with COVID-19 and determined their association with disease severity and 30-day mortality.

Prophylactic fresh frozen plasma and platelet transfusion have a prothrombotic effect in patients with liver disease.

Background And Aims: Patients with liver disease acquire complex changes in their hemostatic system, resulting in prolongation of the international normalized ratio and thrombocytopenia. Abnormalities in these tests are commonly corrected with fresh frozen plasma (FFP) or platelet transfusions before invasive procedures. Whether these prophylactic transfusions are beneficial and truly indicated is increasingly debated.

Efficacy of pro- and anticoagulant strategies in plasma of patients undergoing hepatobiliary surgery.

Background: In vitro efficacy of pro- and antihemostatic drugs is profoundly different in patients with compensated cirrhosis and in those who have cirrhosis and are critically ill.

Objectives: Here we assessed the efficacy of pro- and anticoagulant drugs in plasma of patients undergoing hepato-pancreato-biliary (HPB) surgery, which is associated with unique hemostatic changes.

Methods: We performed in vitro analyses on blood samples of 60 patients undergoing HPB surgery and liver transplantation: 20 orthotopic liver transplantations, 20 partial hepatectomies, and 20 pylorus-preserving pancreaticoduodenectomies.