scholarly journals Increased bleeding risk associated with the use of recombinant human activated protein C in patients with advanced liver disease

Critical Care ◽  
2008 ◽  
Vol 12 (1) ◽  
pp. 405 ◽  
Author(s):  
Adam Keene ◽  
Thomas Kawano ◽  
Syed Anees ◽  
Julie Chen
Keyword(s):  
Liver Disease ◽  
Protein C ◽  
Activated Protein C ◽  
Bleeding Risk ◽  
Advanced Liver Disease

scholarly journals Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation

Blood ◽  
1982 ◽  
Vol 60 (1) ◽  
pp. 261-264 ◽  
Author(s):  
JH Griffin ◽  
DF Mosher ◽  
TS Zimmerman ◽  
AJ Kleiss
Keyword(s):  
Liver Disease ◽  
Serine Protease ◽  
Vitamin K ◽  
Protein C ◽  
Activated Protein C ◽  
Coagulation System ◽  
Antigen Concentration ◽  
Intravascular Coagulation ◽  
The Mean

Abstract Activated protein C is a potent anticoagulant and profibrinolytic enzyme that can be derived from the vitamin-K-dependent serine protease zymogen, protein C, by the action of thrombin. Protein C antigen concentration was determined in plasmas from normals (n = 40) and from 38 patients with intravascular coagulation as evidenced by positive FDP (greater than micrograms/ml). Plasma protein C was 4 micrograms/ml in normals and was significantly depressed (less than 2 SD below the mean of normals) in 19 of the 38 patients. Of 15 patients with suspected intravascular coagulation but normal FDP, protein C was decreased in 5 individuals; 3 of these 5 patients had liver disease. Based on these results, we suggest that extensive activation of the coagulation system in vivo causes a significant consumption of protein C, presumably due to its activation by thrombin and subsequent clearance.

Periprocedural Bleeding Risk Assessment in Chronic Liver Disease

2017 ◽  
Vol 01 (04) ◽  
pp. 306-312
Author(s):  
Brett Fortune ◽  
David Madoff ◽  
Benjamin May
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Blood Product ◽  
Bleeding Risk ◽  
International Normalized Ratio ◽  
Chronic Liver ◽  
Alternative Methods ◽  
Advanced Liver Disease ◽  
Potential Harm ◽  
Clotting Disorder

AbstractInvasive procedures are common in the management of cirrhosis-related chronic liver disease (CLD). Assessing bleeding risk prior to these procedures is challenging because of commonly seen laboratory abnormalities among traditional testing used to evaluate bleeding risk in patients with advanced liver disease. However, this ‘coagulopathy’ seen in advanced liver disease is not a true bleeding or clotting disorder. The prothrombin time/international normalized ratio (PT/INR) test is frequently elevated in CLD patients, but has been shown to poorly correlate with bleeding risk in this population. A traditional interpretation of this laboratory test can lead to unnecessary transfusion of blood product, procedure delay, or even potential harm to the patient. An understanding of the ‘coagulopathy’ of advanced liver disease and alternative methods, to more accurately assess bleeding risk, allows clinicians to treat safely CLD patients.

scholarly journals Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5970-5978 ◽  
Author(s):  
Laurent O. Mosnier ◽  
Antonella Zampolli ◽  
Edward J. Kerschen ◽  
Reto A. Schuepbach ◽  
Yajnavalka Banerjee ◽  
...  
Keyword(s):  
Protein C ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Bleeding Risk ◽  
Endothelial Protein C Receptor ◽  
Antithrombotic Activity ◽  
Cytoprotective Activity ◽  
Protease Activated Receptor 1

Abstract Activated protein C (APC) reduces mortality in severe sepsis patients. APC exerts anticoagulant activities via inactivation of factors Va and VIIIa and cytoprotective activities via endothelial protein C receptor and protease-activated receptor-1. APC mutants with selectively altered and opposite activity profiles, that is, greatly reduced anticoagulant activity or greatly reduced cytoprotective activities, are compared here. Glu149Ala-APC exhibited enhanced in vitro anticoagulant and in vivo antithrombotic activity, but greatly diminished in vitro cytoprotective effects and in vivo reduction of endotoxin-induced murine mortality. Thus, residue Glu149 and the C-terminal region of APC's light chain are identified as functionally important for expression of multiple APC activities. In contrast to Glu149Ala-APC, 5A-APC (Lys191-193Ala + Arg229/230Ala) with protease domain mutations lacked in vivo antithrombotic activity, although it was potent in reducing endotoxin-induced mortality, as previously shown. These data imply that APC molecular species with potent antithrombotic activity, but without robust cytoprotective activity, are not sufficient to reduce mortality in endotoxemia, emphasizing the need for APC's cytoprotective actions, but not anticoagulant actions, to reduce endotoxin-induced mortality. Protein engineering can provide APC mutants that permit definitive mechanism of action studies for APC's multiple activities, and may also provide safer and more effective second-generation APC mutants with reduced bleeding risk.

Activated protein C based therapeutic strategies in chronic diseases

2014 ◽  
Vol 111 (04) ◽  
pp. 610-617 ◽  
Author(s):  
Fabian Bock ◽  
Khurrum Shahzad ◽  
Nathalie Vergnolle ◽  
Berend Isermann
Keyword(s):  
Chronic Diseases ◽  
Protein C ◽  
Therapeutic Agent ◽  
Regulation Of Gene Expression ◽  
Activated Protein C ◽  
Bleeding Risk ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Cytoprotective Agent

SummaryActivated protein C (aPC) is a natural anticoagulant and a potent antiinflammatory and cytoprotective agent. At the expense of increased bleeding risk aPC has been used – with some success – in sepsis. The design of cytoprotective-selective aPC variants circumvents this limitation of increased bleeding, reviving the interest in aPC as a therapeutic agent. Emerging studies suggest that aPC’s beneficial effects are not restricted to acute illness, but likewise relevant in chronic diseases, such as diabetic nephropathy, neurodegeneration or wound healing. Epigenetic regulation of gene expression, reduction of oxidative stress, and regulation of ROS-dependent transcription factors are potential mechanisms of sustained cytoprotective effects of aPC in chronic diseases. Given the available data it seems questionable whether a unifying mechanism of aPC dependent cytoprotection in acute and chronic diseases exists. In addition, the signalling pathways employed by aPC are tissue and cell specific. The mechanistic insights gained from studies exploring aPC’s effects in various diseases may hence lay ground for tissue and disease specific therapeutic approaches. This review outlines recent investigations into the mechanisms and consequences of long-term modulation of aPC-signalling in models of chronic diseases.

Engineering activated protein C to maximize therapeutic efficacy

2015 ◽  
Vol 43 (4) ◽  
pp. 691-695 ◽  
Author(s):  
Louise M. Quinn ◽  
Clive Drakeford ◽  
James S. O’Donnell ◽  
Roger J.S. Preston
Keyword(s):  
Clinical Trials ◽  
Protein Engineering ◽  
Inflammatory Disease ◽  
Therapeutic Efficacy ◽  
Protein C ◽  
Thrombus Formation ◽  
Activated Protein C ◽  
Bleeding Risk ◽  
Protective Role ◽  
Chronic Inflammatory Disease

The anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease. These properties have been exploited to therapeutic effect in diverse animal models of inflammatory disease, wherein recombinant APC administration has proven to effectively limit disease progression. Subsequent clinical trials led to the use of recombinant APC (Xigris) for the treatment of severe sepsis. Although originally deemed successful, Xigris was ultimately withdrawn due to lack of efficacy and an unacceptable bleeding risk. Despite this apparent failure, the problems that beset Xigris usage may be tractable using protein engineering approaches. In this review, we detail the protein engineering approaches that have been utilized to improve the therapeutic characteristics of recombinant APC, from early studies in which the distinct anti-coagulant and signalling activities of APC were separated to reduce bleeding risk, to current attempts to enhance APC cytoprotective signalling output for increased therapeutic efficacy at lower APC dosage. These novel engineered variants represent the next stage in the development of safer, more efficacious APC therapy in disease settings in which APC plays a protective role.

scholarly journals Thrombocytopenia and Hemostatic Changes in Acute and Chronic Liver Disease: Pathophysiology, Clinical and Laboratory Features, and Management

2021 ◽  
Vol 10 (7) ◽  
pp. 1530
Author(s):  
Rüdiger E. Scharf
Keyword(s):  
Platelet Count ◽  
Liver Disease ◽  
Chronic Liver Disease ◽  
Bleeding Risk ◽  
Chronic Liver ◽  
Controversial Issues ◽  
Advanced Liver Disease ◽  
Platelet Destruction ◽  
Clinical Consequences ◽  
Hepatic Synthesis

Thrombocytopenia, defined as a platelet count <150,000/μL, is the most common complication of advanced liver disease or cirrhosis with an incidence of up to 75%. A decrease in platelet count can be the first presenting sign and tends to be proportionally related to the severity of hepatic failure. The pathophysiology of thrombocytopenia in liver disease is multifactorial, including (i) splenomegaly and subsequently increased splenic sequestration of circulating platelets, (ii) reduced hepatic synthesis of thrombopoietin with missing stimulation both of megakaryocytopoiesis and thrombocytopoiesis, resulting in diminished platelet production and release from the bone marrow, and (iii) increased platelet destruction or consumption. Among these pathologies, the decrease in thrombopoietin synthesis has been identified as a central mechanism. Two newly licensed oral thrombopoietin mimetics/receptor agonists, avatrombopag and lusutrombopag, are now available for targeted treatment of thrombocytopenia in patients with advanced liver disease, who are undergoing invasive procedures. This review summarizes recent advances in the understanding of defective but at low level rebalanced hemostasis in stable cirrhosis, discusses clinical consequences and persistent controversial issues related to the inherent bleeding risk, and is focused on a risk-adapted management of thrombocytopenia in patients with chronic liver disease, including a restrictive transfusion regimen.

The Spectrum of Disease Severity in Cirrhosis and Its Implications for Hemostasis

2020 ◽  
Vol 46 (06) ◽  
pp. 716-723
Author(s):  
Matthew J. Stotts ◽  
Ton Lisman ◽  
Nicolas M. Intagliata
Keyword(s):  
Liver Disease ◽  
Bleeding Risk ◽  
Decompensated Cirrhosis ◽  
Advanced Liver Disease ◽  
Critical Knowledge ◽  
Compensated Cirrhosis ◽  
Thrombotic Complications ◽  
Disease Experience ◽  
The Many ◽  
Shed Light

AbstractBleeding and thrombosis are both common complications that patients with advanced liver disease experience. While hemostatic pathways remain largely intact with cirrhosis, this balance can quickly shift in the direction of bleeding or clotting in an unpredictable manner. A growing body of literature is attempting to shed light on difficult scenarios that clinicians often face, ranging from predicting and mitigating bleeding risk in those who need invasive procedures to determining the best strategies to manage both bleeding and thrombotic complications when they occur. Studies examining hemostasis in those with advanced liver disease, however, often include heterogeneous cohorts with varied methodology. While these studies often select a cohort of all types and degrees of cirrhosis, emerging evidence suggests significant differences in underlying systemic inflammation and hemostatic abnormalities among specific phenotypes of liver disease, ranging from compensated cirrhosis to decompensated cirrhosis and acute-on-chronic liver failure. It is paramount that future studies account for these differing disease severities if we hope to address the many critical knowledge gaps in this field.

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