Abstract
BackgroundIncrease in tissue factor (TF) and loss in thrombomodulin (TM) antigen levels has been described in various inflammatory disorders. The functional consequences of such changes in antigen concentrations in the coagulation balance are, however, not known. This study was designed to assess the consequences of inflammation-driven organ specific functional properties of the procoagulant response.MethodsTissue specific procoagulant activity was assessed by adding tissue homogenate to normal human pool plasma and recording of the thrombin generation curve. The new technique was subsequently applied on two inflammation driven animal models: 1) mouse lipopolysaccharide (LPS) induced endotoxemia and 2) spontaneously hypertensive rats exposed to environmental air pollution (particulate matter (PM).ResultsAddition of lung tissue from untreated animals to human plasma suppressed the endogenous thrombin potential (ETP) (175 ± 61 vs. 1437 ± 112 nM.min for control). This inhibitory effect was due to TM, because a) it was absent in protein C deficient plasma and b) lungs from TMpro/pro mice allowed full thrombin generation (ETP: 1686 ± 209 nM.min). The inhibitory effect of TM was lost after LPS administration to mice, which induced TF activity in lungs of C57Bl/6 mice as well as increased the ETP (941 ± 523 vs. 194 ± 159 nM.min for control). Another pro-inflammatory stimulus, PM dose-dependently increased TF in the lungs of spontaneously hypertensive rats at 4 and 48 hours after PM exposure. The ETP increased up to 48 hours at the highest concentration of PM (1441 ± 289 nM.min vs. saline: 164 ± 64 nM.min, p < 0.0001), suggesting a concentration- and time dependent reduction in TM activity.ConclusionInflammation associated procoagulant effects in tissues are dependent on variations in activity of the TF-TM balance. The application of these novel organ specific functional assays is a useful tool to monitor inflammation-driven shifts in the coagulation balance within animal or human tissues.
Highlights
The inflammation associated procoagulant response is a characteristic feature of innate immunity and a reflection of the crosstalk between inflammation and blood coagulation
A loss of endogenous anticoagulant activity is proposed to occur during inflammation, mainly based on in vitro studies showing loss in thrombomodulin (TM) and endothelial protein C receptor (EPCR) antigen in cultured endothelial cells [4,5,6]
Study design Three different studies were undertaken to study the effects of inflammation on tissue-specific hypercoagulability: 1. Development of a new method to assess tissue factor (TF) and TM activity in tissue homogenates
Summary
The inflammation associated procoagulant response is a characteristic feature of innate immunity and a reflection of the crosstalk between inflammation and blood coagulation. During acute inflammatory conditions, such as sepsis, the procoagulant response is characterized by increased cellular expression of tissue factor (TF) [1,2,3], the physiological trigger of coagulation. In chronic inflammatory diseases, including atherosclerosis and cancer, increased expression of TF and reduced expression of TM have been observed [8,9,10,11]. In such chronic conditions, a disturbed balance in pro- and anticoagulant activities is thought to have an unfavourable effect on disease activity [11]. This study was designed to assess the consequences of inflammation-driven organ specific functional properties of the procoagulant response
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