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J. Köhler et al.
   tion for low contact factor levels is downregulation of gene expression in the liver, as shown in the present study for F12 and Klkb1 genes in the mouse sepsis model. The knowledge about the pathophysiological role of contact factor gene expression is important for the understanding of their general functions in infection. Expression of Klkb1 was quickly decreased due to invasive infection in mice and accompanied by a fast decrease in the protein in plas-
ma. In addition, an earlier study has shown that the clear- ance rate of PK by the liver is significantly increased dur- ing the acute phase reaction.35 Both mechanisms could contribute to low PK levels in plasma of septic patients, and this suggests that the fast reduction of PK is part of the physiological acute phase response, which supports the antifibrinolytic state. The role of the acute phase response is to enhance host defense to prevent injury of the host
 AB
C
 D
E
Figure 5. Effect of human congenital factor XII (FXII) or plasma prekallikrein (PPK) deficiency on fibrinolysis induced by strep- tokinase or S. pyogenes bacteria. (A) A clot was derived in normal, FXII- or PPK-defi- cient plasma by thromboplastin (PT)- reagent and time until clot lysis was meas- ured after addition of streptokinase, uPA or tPA. (B) A clot was derived in normal, FXII- or PPK-deficient (def) plasma that was, if indi-
FG
H
cated, pre-incubated with
(75 mg/mL), PKSI (10 mM), FXIIa (50 mg/mL) or PK (50 mg/mL). Time until clot lysis was measured after addition of streptokinase. (C) Growing S. pyogenes (2x108 CFU/mL) were mixed with plasma, and thrombin was used to form a stable clot. The plasma clot was overlaid with PBS and D-dimer concentration in the super- natant was measured after different time points, using an ELISA. (D and E) Representative western blot analysis of fib- rinogen incubated for up to 30 minutes with plasminogen+streptokinase (Plg/Ska), plasminogen+streptokinase+PPK (Plg/Ska/PPK), Plasmin, or FXII+PPK (FXII/PPK) (F and G) relative levels of uncleaved fibrinogen (Fbg), quantified by densitometry from three independent experiments. (H) Plasma clots were induced by thrombin, fixed and analyzed by Scanning electron microscopy. Bars repre- sent 2 mm. *P≤0.05; **P≤0.01; ***P≤0.001; ****P≤0.0001. min: min- utes.
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