Page 273 - Haematologica May 2020

Different functions for FXII and PK in sepsis
within the process of killing bacteria.1 A procoagulant state with inhibition of fibrinolysis may help to contain the bacteria at the primary site of infection. The impairment of fibrinolysis is mediated by different mechanisms, i.e. by decreasing liver synthesis of anticoagulants such as antithrombin III,36 or increasing production of fibrinolysis
inhibitors, such as thrombin-activatable fibrinolytic inhibitor (TAFI)37 or plasminogen-activator-inhibitor 1 (PAI1).38,39 Our investigations suggest that down-regulated Klkb1 expression during infection likewise contributes to inhibited fibrinolysis.
The intrinsic coagulation pathway does not contribute
AB
CD
E
Figure 6. Antisense-oligonucleotide (ASO)-mediated plasma prekallikrein (PPK) depletion reduced bacterial escape and inhibited bacteria-triggered fibrinolysis in mouse plasma clots. (A and B) Plasma from four mice per group was pooled and mixed with 1x107 colony forming units (CFU)/mL S. pyogenes, a stable clot was induced by addition of thrombin and CaCl2, and overlaid with PBS, containing 1% plasma. After 4 hours (h), the bacterial loads in the supernatant (A) and homoge- nized clots (B) were determined by plating. N=4. *P=0.0323; ****P<0.0001. (C) PAP complexes or plasminogen content (D) were determined in EDTA plasma from infected control- or PPK-ASO treated mouse, n=5 per group. (E) Plasma was mixed with 1x109 CFU/mL S. pyogenes and clot formation was induced by addition of thrombin and CaCl2. After 4 h of incubation at 37°C, clots were fixed and analyzed by Scanning electron microscopy. Bars represent 2 mm. PK: plasma kallikrein; n.s. not significant.
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