Plasma levels of endothelial protein C receptor respond to anticoagulant treatment

Abstract

The endothelial protein C receptor (EPCR) facilitates protein C activation and plays a protective role in the response to Escherichia coli-mediated sepsis in primates. Previously, a soluble form of EPCR (sEPCR) in human plasma was characterized, and several studies indicated that generation of sEPCR is regulated by inflammatory mediators, including thrombin-mediated up-regulation of surface metalloproteolytic activity in vitro. This study addressed the question of whether plasma sEPCR levels reflect changes in thrombin generation in patients undergoing anticoagulant treatment. The sEPCR levels in patients treated with coumarintype oral anticoagulants were significantly lower than those in healthy asymptomatic adult volunteers (105.3 ؎ 70.8 ng/mL [n ‫؍‬ 55] versus 165.8 ؎ 115.8 ng/mL [n ‫؍‬ 200]; P < .0001). A similar decline in plasma sEPCR levels was found in patients treated with unfractionated heparin. In healthy volunteers, sEPCR levels declined to about 100 ng/mL within 3 days after initiation of an 8-day period of warfarin administration and increased within 2 days after its cessation. Plasma sEPCR levels returned to pretreatment values within 1 week, and the changes in plasma sEPCR levels mirrored changes in values for international normalized ratios. A similar decline in sEPCR levels with time was observed in 7 patients beginning treatment with warfarin for a thrombotic disorder. Prothrombin fragment 1 ؉ 2 levels also decreased in volunteers and patients given warfarin. These results show that plasma sEPCR levels decline in response to treatment with anticoagulants whose mechanism of action is known to decrease in vivo thrombin production. (Blood. 2002;99:526-530)

A phase II trial of thalidomide in patients with refractory endometrial cancer and correlation with angiogenesis biomarkers: A Gynecologic Oncology Group study

“…A functional, soluble form of EPCR (sEPCR) circulates in plasma that is a proteolytic product of the membrane-bound EPCR. sEPCR levels are elevated in patients with systemic inflammatory diseases and there is evidence that sEPCR levels increase as a result of thrombin activity [40][41]. Many cancers over-express tissue factor, the membrane receptor that is ultimately responsible for in vivo thrombin generation and contributes to tumor invasive potential [42].…”

“…Thalidomide has potent antiinflammatory activity by virtue of its ability to inhibit generation of pro-inflammatory cytokines, down-regulate granulocyte activity, and stimulate cytotoxic Th1 T cell proliferative responses with ensuing production of interferon γ [14]. Modulation of an inflammatory environment is reflected in changes in the soluble endothelial protein C receptor (sEPCR) biomarker, a member of the protein C anti-coagulant and anti-inflammatory pathway [15][16]. Changes in these biomarkers may reflect either selective cancer regression or more systemic responses as a result of therapy.…”

The relation between soluble endothelial protein C receptor and factor VIII levels and FVIII/sEPCR index in healthy infants

“…Increased levels of sEPCR in plasma lead to dysfunction of the EPCR-mediated coagulation [5]. sEPCR levels vary among healthy subjects, and the bimodal distribution has been reported several times [12][13][14]. A recent study showed a negative relationship between sEPCR levels and an individual's age; that is, sEPCR levels of healthy children were found to be higher than those of healthy adults (14).…”

“…Increased plasma sEPCR levels were found associated with an increased risk of venous thrombosis and thrombin generation [12,15]. Further, it was reported that increased FVIII levels are an important risk factor for venous and arterial thrombosis [11,16].…”

Oral anticoagulation reduces activated protein C less than protein C and other vitamin K–dependent clotting factors

“…9,10 Oral anticoagulant therapy causes a decrease in circulating soluble endothelial protein C receptor. 11 APC is a physiologic anticoagulant and anti-inflammatory agent that was recently approved by the Food and Drug Administration (FDA) for therapy of severe sepsis because it substantially reduces sepsis-related mortality. 12 Low levels of circulating APC were recently suggested to be a risk factor for venous thrombosis.…”