scholarly journals Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4886-4893 ◽  
Author(s):  
Marlene E. Starr ◽  
Junji Ueda ◽  
Hitoshi Takahashi ◽  
Hartmut Weiler ◽  
Charles T. Esmon ◽  
...  
Keyword(s):  
Mortality Rate ◽  
High Mortality ◽  
Protein C ◽  
Low Dose ◽  
Activated Protein C ◽  
Aged Mice ◽  
Fibrin Formation ◽  
Pathway Activation ◽  
Age Dependent ◽  
Young Mice

AbstractThe protein C (PC) pathway is an important anticoagulant mechanism that prevents thrombosis during the systemic inflammatory response. Thrombomodulin (TM), an endothelial cell membrane receptor, accelerates the conversion of PC to activated protein C (APC), which leads to the down-regulation of thrombin production and fibrin formation. Induction of acute endotoxemia in young and aged mice with a low dose of bacterial endotoxin lipopolysaccharide (LPS, 2.5 mg/kg) caused a high mortality rate in aged (80%) but not young (0%) mice. After injection with this dose of LPS, fibrin formation was significantly elevated only in aged mice, plasma APC levels were increased only in young mice, and TM expression was profoundly depressed in the aged. The increased thrombosis, suppressed APC level, and decreased TM expression were not observed in young mice receiving a higher dose of LPS (20 mg/kg), which resulted in a mortality rate (78%) equivalent to that seen in aged mice with the low-dose LPS. Mutant mice with reduced TM showed significantly less plasma APC and increased fibrin formation compared with wild-type mice after LPS. These results demonstrate that PC pathway activation is suppressed with aging and is partly responsible for age-associated thrombosis and high mortality during endotoxemia.

scholarly journals Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis

2015 ◽  
Vol 308 (2) ◽  
pp. H83-H91 ◽  
Author(s):  
Marlene E. Starr ◽  
Hitoshi Takahashi ◽  
Daiki Okamura ◽  
Brittany A. Zwischenberger ◽  
Amy A. Mrazek ◽  
...  
Keyword(s):  
Protein C ◽  
Cecal Ligation ◽  
Activated Protein C ◽  
Abdominal Sepsis ◽  
Activation Mechanism ◽  
Experimental Sepsis ◽  
Enhanced Coagulation ◽  
Aged Mice ◽  
Age Dependent ◽  
Young Mice

Sepsis is a life-threatening clinical condition that is particularly serious among the elderly who experience considerably higher mortality rates compared with younger patients. Using a sterile endotoxemia model, we previously reported age-dependent mortality in conjunction with enhanced coagulation and insufficient levels of anti-coagulant factor activated protein C (aPC). The purpose of the present study was to further investigate the mechanisms for age-dependent coagulation and aPC insufficiency during experimental sepsis. Intra-abdominal sepsis was induced by cecal ligation and puncture (CLP) using 21 or 16 gauge (G) needles (double-puncture) on young (4 to 6 mo old) and aged (20 to 25 mo old) male C57BL/6 mice. When compared with young mice, aged mice showed significantly increased mortality (92% vs. 28%), systemic inflammation, and coagulation in the lung and kidney after 21G CLP. Young mice with more severe CLP (16G) showed a mortality rate and inflammation equivalent to aged mice with 21G CLP; however, enhanced coagulation and kidney dysfunction were significant only in the aged. In young mice, increased levels of aPC after CLP were coupled with reduced levels of protein C (PC), suggesting the conversion of PC to aPC; however, PC and aPC levels remained unchanged in aged mice, indicating a lack of PC to aPC conversion. Activation of fibrinolysis, determined by plasma d-dimer levels, was similar regardless of age or CLP severity, and plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, showed severity-dependent induction independent of age. These results suggest that enhanced coagulation in aged mice during sepsis is due to dysfunction of the PC activation mechanism.

Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

2007 ◽  
Vol 97 (06) ◽  
pp. 938-943 ◽  
Author(s):  
Sigurd Liestøl ◽  
Marie-Christine Mowinckel ◽  
H. Coen Hemker ◽  
Per-Morten Sandset ◽  
Anette Eilertsen
Keyword(s):  
Hormone Therapy ◽  
Protein C ◽  
Low Dose ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
System Sensitivity ◽  
Conventional Dose ◽  
Apc Resistance ◽  
The Difference ◽  
Progestin Therapy

SummaryRecent studies have shown that hormone therapy (HT) is associated with an acquired resistance to activated protein C (APC). The aims of the present study were to evaluate a possible dose-response relationship and differential effects of different HT regimens on functionality of the APC system. Two hundred two healthy women were randomly assigned to receive treatment for 12 weeks with tablets containing either low-dose HT containing 1 mg 17β-oestradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17β-oestradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). Normalized APC system sensitivity ratios (nAPCsr) were determined in plasma collected at baseline and after 12 weeks using a thrombin generation-based APC resistance test probed with either recombinant APC (rAPC) or thrombomodulin (rTM). NAPCsr increased in both the conventional- and low-dose HT groups, consistent with reduced sensitivity to APC. The increase was slightly more pronounced in the conventional-dose group, but the difference between the two HT groups was not statistically significant. The sensitivity to APC was only marginally altered in those allocated to tibolone. Consequently, tibolone showed a different phenotype as compared with the low-dose HT group. A small increase in nAPCsr with both rAPC and rTM was seen in the raloxifene-group, but the increase was less than in the low-dose HT group. Our findings indicate that oestrogen-progestin therapy induces an APC resistant phenotype, which may be related to dose, whereas tibolone and raloxifene only marginally alter the sensitivity to APC.

Activated Protein C, Sepsis, and the Innate Immune Response to Infection

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-43-SCI-43
Author(s):  
Hartmut Weiler ◽  
John H. Griffin
Keyword(s):  
Bone Marrow ◽  
Severe Sepsis ◽  
Protein C ◽  
Second Generation ◽  
Low Dose ◽  
Activated Protein C ◽  
Innate Immune ◽  
Great Promise ◽  
High Dose ◽  
Increased Risk

Abstract Abstract SCI-43 The phase 3 PROWESS clinical trial in 2001 resulted in approval of recombinant human activated protein C (APC) using low-dose, 96 hour infusion therapy to reduce mortality for adult severe sepsis linked to bacterial infection (1). In that trial, APC reduced mortality from 30.8% to 24.7%, an absolute mortality reduction of 6.1% (19.4% relative risk reduction), but this therapy carried a risk of serious bleeding (4.0 vs. 1.5%, p=0.06). Trials of APC therapy for less than severe adult or pediatric sepsis failed to show benefit but confirmed increased risk for serious bleeding. Subsequently, 10 years after the PROWESS trial, the similarly designed large trial (PROWESS SHOCK) (2) failed to document therapeutic efficacy in adult severe sepsis, reporting mortalities of 26.4% vs. 24.2% and, curiously, no increased risk of serious bleeding (1.2 vs. 1.0%, p=0.81). Recombinant APC was thus withdrawn from the market in late 2011. A simple comparison of PROWESS to PROWESS-SHOCK is confounded by significant improvements in ICU standard of care for severe sepsis over a decade. These two trials were notable in being limited to therapy using low-dose APC infusion for four days. The success of PROWESS stimulated major research advances in 2002–2012 for understanding APC's in vitro and in vivo mechanisms of action. In preclinical work, APC is highly effective for sepsis, non-infectious inflammatory disease, ischemic stroke and neurodegenerative disorders. This presentation will review current knowledge about mechanisms for APC's antithrombotic and cellular cytoprotection, about new insights that might help explain the absence of efficacy in PROWESS-SHOCK, and about possible avenues towards translating the benefits of APC seen in preclinical studies to patients. This presentation will discuss the rationale for use of second generation APC variants that may reduce the risk of bleeding while retaining beneficial anti-inflammatory and cytoprotective functions. Recent preclinical animal studies indicate that such second-generation APC variants might widen the time-window of opportunity for successful therapies, including for lethal infections. Remarkably, APC reduces mortality caused by high-dose total body radiation in mice by preserving bone marrow cells (3). This presentation will review cellular and molecular mechanisms by which APC affects the response of bone marrow-derived innate immune cells to stress induced by infection or radiation. This presentation will provide evidence for the existence of a previously unrecognized role of coagulation Factor V as a modifier of the response to sepsis therapy with APC. Based on APC's direct cellular effects, one would speculate that the use of second generation APC variants given in high-dose bolus regimens holds great promise for multiple maladies. Disclosures: Weiler: BloodCenter of Wisconsin: Patents & Royalties.

Clinical Experience with Drotrecogin Alfa in Treating Gram-Positive and -Negative Pathogens in Patients with Severe Sepsis

2004 ◽  
Vol 52 (7) ◽  
pp. 470-474 ◽  
Author(s):  
Lawrence A. Cone ◽  
Richard A. Stone ◽  
Kenneth Jesser ◽  
Richard Nelson
Keyword(s):  
Severe Sepsis ◽  
Mortality Rate ◽  
Organ Failure ◽  
Protein C ◽  
Antimicrobial Agents ◽  
Survival Rates ◽  
Activated Protein C ◽  
Gram Positive ◽  
Gram Negative ◽  
Local Disease

BackgroundNewer concepts in the management of severe sepsis and, in particular, in the understanding of the relationship between proinflammatory and procoagulant activities during severe infection have led to the introduction of activated protein C (drotrecogin) into the therapeutic program. The combination of effective antimicrobial therapy, aggressive supportive care, and efforts to antagonize procoagulants and inhibitors of fibrinolysis was used in this study.MethodsWe treated 12 patients with severe sepsis using this combination of antimicrobial agents and drotrecogin. All patients presented with hypotension and organ failure and some with multiple organ failure. Infected patients were separated into those with gram-positive and those with gram-negative infections.ResultsIn contrast to an expected mortality rate of nearly 40% in this group of patients, only 2 (9%) expired. Both deaths were due to infection by gram-negative organisms in patients with complicated abdominal infections and concurrent cancer. All patients with gram-positive organisms survived.ConclusionThose patients with infections caused by gram-positive organisms seemed to have a better prognosis than those with gram-negative infections, perhaps because their illnesses are less complicated by local disease. Although our study is small, it suggests that activated protein C will have a significant beneficial effect on the future treatment of severe sepsis and can reduce the mortality rate significantly. Further improvement in survival rates will require more effective treatment of local disease and associated noninfectious ailments.

Effect of recombinant activated protein C and low-dose heparin on neutrophil-endothelial cell interactions in septic shock*

2006 ◽  
Vol 34 (8) ◽  
pp. 2207-2212 ◽  
Author(s):  
Linda A. Kirschenbaum ◽  
Wilma Correa Lopez ◽  
Patricia Ohrum ◽  
Anita Tsen ◽  
John Khazin ◽  
...  
Keyword(s):  
Septic Shock ◽  
Endothelial Cell ◽  
Protein C ◽  
Low Dose ◽  
Activated Protein C ◽  
Cell Interactions ◽  
Dose Heparin ◽  
Low Dose Heparin

Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study

The Lancet ◽  
1999 ◽  
Vol 354 (9195) ◽  
pp. 2036-2040 ◽  
Author(s):  
Jan Rosing ◽  
Saskia Middeldorp ◽  
Joyce Curvers ◽  
M Christella L GDlig; Thomassen ◽  
Gerry AF Nicolaes ◽  
...  
Keyword(s):  
Oral Contraceptives ◽  
Protein C ◽  
Low Dose ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
Dose Oral

Thrombin spatial distribution determines Protein C activation during hemostasis and thrombosis

Blood ◽  
2021 ◽  
Author(s):  
Tanya T. Marar ◽  
Chelsea N. Matzko ◽  
Jie Wu ◽  
Charles Esmon ◽  
Talid Sinno ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
Protein C ◽  
Thrombin Generation ◽  
Jugular Vein ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Fibrin Formation

Rebalancing of the hemostatic system by targeting endogenous anticoagulant pathways, like the Protein C system, is being tested as a means of improving hemostasis in patients with hemophilia. Recent intravital studies of hemostasis demonstrated that, in some vascular contexts, thrombin activity is sequestered to the extravascular compartment. These findings raise important questions about the context-dependent contribution of activated Protein C (aPC) to the hemostatic response since Protein C activation occurs on the surface of endothelial cells. Here, we used a combination of pharmacologic, genetic, imaging, and computational approaches to examine the relationships among thrombin spatial distribution, Protein C activation, and aPC anticoagulant function. We found that inhibition of aPC activity, either in mice harboring the Factor V-Leiden mutation or infused with an aPC blocking antibody, significantly enhanced fibrin formation and platelet activation in a microvascular injury model, consistent with aPC's role as an anticoagulant. In contrast, inhibition of aPC activity had no effect on hemostasis following penetrating injury of the mouse jugular vein. Computational studies showed that differences in blood velocity, injury size, and vessel geometry determine the localization of thrombin generation and, consequently, the extent of Protein C activation. Computational predictions were tested in vivo and showed that when thrombin generation occurred intravascularly, without penetration of the vessel wall, inhibition of aPC significantly increased fibrin formation in the jugular vein. Together, these studies show the importance of thrombin spatial distribution in determining Protein C activation during hemostasis and thrombosis.

Low dose whole lung radiotherapy for older patients with corona virus 19 disease (COVID-19) pneumonitis: practical protocol by the International Geriatric Radiotherapy Group (Preprint)

2020 ◽  
Author(s):  
Nam Nguyen ◽  
Meritxell Arenas ◽  
Te Vuong ◽  
Alice Zamagni ◽  
Vincent Vinh-Hung ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Inflammatory Response ◽  
High Mortality ◽  
Older Patients ◽  
Low Dose ◽  
Artificial Ventilation ◽  
Ordinal Scale ◽  
Co Morbidity ◽  
Lung Radiotherapy ◽  
The Impact

BACKGROUND Coronavirus disease 19 (COVID-19) carry a high mortality rate among older patients and minorities such as ethnic Africans and Latinos. The chronic baseline systemic inflammation of older patients and minorities may make them more vulnerable to the cytokines storm generated by the viral infection in addition to preexisting co-morbidity. Even though multiple organs failure result from the cytokine storm, pneumonia and respiratory failure often lead to death. OBJECTIVE Low dose whole lung radiotherapy (LDWLRT) may modulate the inflammatory response and may decrease the need for artificial ventilation, thus improving mortality rate. METHODS A phase I-II prospective trials enrolling 500 patients, 65 years old or older from 25 countries will be conducted to investigate the impact of LDWLRT on mortality rate of COVID-19 patients. The patients who will be selected would have developed pneumonias but did not require artificial ventilation. These patients will be followed for a year after receiving this treatment. Their physical activities will be monitored through the ordinal scale and will be correlated with their cytokines status and oxygen saturation rate to assess the impact of the residual inflammation on their daily life. Mortality rates between different ethnic group will be compared and correlated with their cytokines response to the virus and number of co-morbidities. RESULTS We postulate that LDWLRT may improve survival rates of all patients by preventing the need for artificial ventilation which is associated with a high mortality. The inflammatory response between different ethnic groups before and following radiotherapy will be valuable to serve as baseline for future prospective pandemic studies as it has not been reported before. CONCLUSIONS Once the study is complete, we may be able to demonstrate that LDWLRT may improve survival through its anti-inflammatory property CLINICALTRIAL NCT 04493294

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