Role of coagulation FVIII in septic peritonitis assessed in hemophilic mice.
BACKGROUND
Inhibition of blood coagulation appears to be an important therapeutic strategy to improve the outcome in sepsis. However, the beneficial effect of anticoagulant treatment in sepsis is solely based on experimental data using inhibitors of the extrinsic coagulant pathway. The role of the intrinsic pathway of coagulation in the pathogenesis of sepsis has not been explored yet.


OBJECTIVE
In the current study, we contribute to determine the role of factor (F)VIII, the key player of the intrinsic coagulant pathway, on host defense against peritonitis.


METHODS
Hemizygous FVIII-deficient mice and their wild-type littermates were challenged with 1 x 10(4) bacteria in a septic peritonitis model.


RESULTS
The intraperitoneal injection of Escherichia coli led to growth and dissemination of bacteria and provoked an inflammatory response as evident from elevated cytokine levels, increased cell influx into tissues, liver necrosis, and endothelialitis resulting in mortality. The FVIII-deficient genotype slightly reduced bacterial outgrowth but had no effect on markers of inflammation and/or survival. In addition, FVIII-deficient mice showed profound activation of coagulation, thereby improving the hemophilic phenotype of FVIII-deficient mice.


CONCLUSIONS
FVIII deficiency slightly modifies host defense in septic peritonitis in mice, but does not influence the final outcome of peritonitis. Therefore, we question the importance of the intrinsic coagulant pathway during sepsis.
Schoenmakers
S H H F
SH
Laboratory for Experimental Internal Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
Brüggemann
L W
LW
Groot
A P
AP
Maijs
S
S
Reitsma
P H
PH
Spek
C A
CA
D000818:Animals; D001777:Blood Coagulation; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000254:growth & development; D005169:Factor VIII / Q000502:physiology*; D006467:Hemophilia A / Q000150:complications; D007109:Immunity; D007249:Inflammation; D008074:Lipoproteins / Q000235:genetics; D051379:Mice; D010538:Peritonitis / Q000097:blood / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D018805:Sepsis / Q000097:blood / Q000209:etiology*; D015996:Survival Rate; D013925:Thromboplastin / Q000235:genetics
D008074:Lipoproteins; D012333:RNA, Messenger; C051928:lipoprotein-associated coagulation inhibitor; D005169:Factor VIII; D013925:Thromboplastin