Abstract
BackgroundA prolonged prothrombin time (PT) is a common feature in sepsis indicating consumptive coagulopathy. ObjectivesTo determine the association between a prolonged PT and aberrations in other host response mechanisms in sepsis. MethodsPatients admitted to the intensive care unit with sepsis were divided in quartiles according to the highest PT value measured within 24 h after admission. The host response was evaluated by measuring 19 plasma biomarkers reflecting pathways implicated in sepsis pathogenesis and by blood leukocyte gene expression profiling. Measurements and Main ResultsOf 1524 admissions for sepsis, 386 (25.3%) involved patients with a normal PT (≤12.7 s); the remaining quartiles entailed 379 (24.9%) patients with a slightly prolonged PT (12.8 ≤ PT ≤ 15.0 s), 383 (25.1%) with an intermediately prolonged PT (15.1 ≤ PT ≤ 17.2 s), and 376 (24.7%) with an extremely prolonged PT (≥17.3 s). While patients with an extremely prolonged PT showed an increased crude mortality up to 1 year after admission, none of the prolonged PT groups was independently associated with 30‐day adjusted mortality. Comparison of the host response between patients with a normal PT or an extremely prolonged PT matched for baseline characteristics including severity of disease showed that an extremely prolonged PT was associated with impaired anticoagulant mechanisms, a more disturbed endothelial barrier integrity and increased systemic inflammation, and blood leukocyte transcriptomes indicating more prominent metabolic reprogramming and protein catabolism. ConclusionA prolonged PT is associated with stronger anomalies in pathways implicated in the pathogenesis of sepsis, suggesting that activation of coagulation impacts other host response mechanisms.
Highlights
Prothrombin time (PT) is a widely used test to detect coagulation abnormalities in critically ill patients.[1,2] The reported incidence of a prolonged prothrombin time (PT), indicative of consumptive coagulopathy, ranges from 30% to 66% in the overall intensive care unit (ICU) population,[3,4] with an even higher incidence in critically ill patients with sepsis.[5]
Consumptive coagulopathy is a common complication in patients with sepsis caused by strong activation of the coagulation system and manifested by a prolonged PT.[1,2,5,6]
While multilevel interactions between mediators of coagulation and other host response mechanisms have been documented in laboratory and animal investigations,[12,13] knowledge of associations between plasmatic coagulation and the dysregulated host response in patients with sepsis is limited
Summary
Prothrombin time (PT) is a widely used test to detect coagulation abnormalities in critically ill patients.[1,2] The reported incidence of a prolonged PT, indicative of consumptive coagulopathy, ranges from 30% to 66% in the overall intensive care unit (ICU) population,[3,4] with an even higher incidence in critically ill patients with sepsis (up to 93%).[5]. Besides PT, platelet counts are commonly used to determine the extent of coagulation activation.[1,2] The recently introduced term “sepsis- associated coagulopathy” is defined by the presence of low platelet counts and a prolonged PT.[6] We previously reported that low platelet counts in ICU patients with sepsis are independently associated with increased mortality and a more disturbed host response.[8] Sepsis patients with platelet counts below 50 × 109/L showed enhanced activation of the cytokine network and the vascular endothelium; a more profound loss of vascular integrity; and a distinct whole-blood leukocyte transcriptome pattern revealing decreased leukocyte adhesion, diapedesis, and extravasation signaling.[8] This observational study provided validity to a series of mouse studies documenting a protective and immune regulatory role of platelets in experimental sepsis.9-11 Considering the pleiotropic functions of platelets beyond their role in hemostasis,9-11 our earlier investigation left unanswered whether coagulation activation per se impacts the host response in patients with sepsis This question is relevant in view of laboratory and animal studies pointing at an extensive cross-talk between coagulation factors and endothelial cell function and inflammation, as well as investigations reporting protection against the lethal consequences of fulminant sepsis by inhibition of components of the coagulation system.[12,13]. In an unbiased approach we compared genome-wide messenger (m)RNA profiles in blood leukocytes obtained from patients with a normal or extremely prolonged PT
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