Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice.
Blood 128(5):721 (2016)
Thrombin-mediated proteolysis is central to hemostatic function but also plays a prominent role in multiple disease processes. The proteolytic conversion of fII to α-thrombin (fIIa) by the prothrombinase complex occurs through 2 parallel pathways: (1) the inactive intermediate, prethrombin; or (...
Activated protein C protects against renal ischaemia/reperfusion injury, independent of its anticoagulant properties.
Thrombosis and Haemostasis 116(1):124 (2016)
Acute renal failure, a serious condition characterised by a drastic decline in renal function, often follows ischaemia/reperfusion (I/R) episodes. I/R is characterised by necrosis, inflammation and activation of coagulation, in concert causing renal tissue damage. In this context, activated prot...
Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling.
Annals of the Lyceum of Natural History of New ... 1370(1):65 (2016)
The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adult murine bone marrow (BM) long-term repopulating hematopoietic stem cells (LT-HSCs), endowed with the highest repopulation and self-renewal potential, expre...
Corrigendum: PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells.
Nature Medicine 22(4):446 (2016)
Plasmodium falciparum adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor.
Cellular Microbiology 17(12):1868 (2015)
Cytoadhesion of Plasmodium falciparum-infected erythrocytes to endothelial protein C receptor (EPCR) is associated with severe malaria. It has been postulated that parasite binding could exacerbate microvascular coagulation and endothelial dysfunction in cerebral malaria by impairing the protein...
Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination.
Journal of the American Society of Nephrology 26(11):2789 (2015)
Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undef...
PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells.
Nature Medicine 21(11):1307 (2015)
Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation related also control retention of endothelial protein...
Dual targeting of therapeutics to endothelial cells: collaborative enhancement of delivery and effect.
FASEB Journal 29(8):3483 (2015)
Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood-tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both e...
Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions.
PLoS Pathogens 11(7):e1005011 (2015)
A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on...
The cytoprotective effects of endogenous activated protein C reduce activation of coagulation during murine pneumococcal pneumonia and sepsis.
Thrombosis Research 135(3):537 (2015)
Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and sepsis. Activated protein C (APC) has been implicated as an important anticoagulant and anti-inflammatory mediator. We here sought to determine the role of the anticoagulant and cytoprotective...
Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis.
American Journal of Physiology - Heart and Circ... 308(2):H83 (2015)
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 coagula...
Blockade of endothelial cell protein C receptor augments factor VIIa hemostatic effect in hemophilia treatment.
Blood 124(19):3031 (2014)
Challenges and priorities for research: a report from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on thrombosis in pediatric cardiology and congenital heart disease.
Circulation 130(14):1192 (2014)
Endothelial cell protein C receptor: a multiliganded and multifunctional receptor.
Blood 124(10):1553 (2014)
Endothelial cell protein C receptor (EPCR) was first identified and isolated as a cellular receptor for protein C on endothelial cells. EPCR plays a crucial role in the protein C anticoagulant pathway by promoting protein C activation. In the last decade, EPCR has received wide attention after i...
Roles of Coagulation and fibrinolysis in angiotensin II-enhanced microvascular thrombosis.
Microcirculation 21(5):401 (2014)
AngII-induced HTN is associated with accelerated thrombus development in arterioles. This study assessed the contributions of different components of the coagulation cascade and fibrinolysis to AngII-mediated microvascular thrombosis.
Light/dye-induced thrombus formation (the time of onset and f...
The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis.
Thrombosis and Haemostasis 111(5):970 (2014)
Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the rol...
Targeting factor Xa and thrombin: impact on coagulation and beyond.
Thrombosis and Haemostasis 111(4):625 (2014)
Great advances have been made in recent years in understanding the haemostatic system and the molecular and cellular basis of thrombus formation. Although directly targeting factor Xa or thrombin (factor IIa) for effective anticoagulation is now well established, evidence has emerged suggesting ...
Platelet endothelial cell adhesion molecule targeted oxidant-resistant mutant thrombomodulin fusion protein with enhanced potency in vitro and in vivo.
Journal of Pharmacology and Experimental Therap... 347(2):339 (2013)
Thrombomodulin (TM) is a glycoprotein normally present in the membrane of endothelial cells that binds thrombin and changes its substrate specificity to produce activated protein C (APC) that has antithrombotic and anti-inflammatory features. To compensate for loss of endogenous TM in pathology,...
Inhibition of endogenous activated protein C attenuates experimental autoimmune encephalomyelitis by inducing myeloid-derived suppressor cells.
Journal of Immunology 191(7):3764 (2013)
Activated protein C (PC) is an anticoagulant involved in the interactions between the coagulation and immune systems. Activated PC has broad anti-inflammatory effects that are mediated through its ability to modulate leukocyte function and confer vascular barrier protection. We investigated the ...
Protein C and acute inflammation: a clinical and biological perspective.
American Journal of Physiology - Lung Cellular ... 305(7):L455 (2013)
The protein C system plays an active role in modulating severe systemic inflammatory processes such as sepsis, trauma, and acute respiratory distress syndrome (ARDS) via its anticoagulant and anti-inflammatory properties. Plasma levels of activated protein C (aPC) are lower than normal in acute ...