Evaluation of Thrombin Generation in the Early Stages of Sepsis in Patients with Hematological Malignancies and Febrile Neutropenia,

Coagulation activation is a consequences of the host response to sepsis. Up-regulation of tissue factor expression and down-regulation of natural anticoagulant and fibrinolytic systems observed in non-clinical and clinical studies of sepsis lead to disseminated intravascular coagulation (DIC), regarded as a contributor to the pathogenesis of sepsis. Nonetheless, clinical strategies targeting coagulation activation have not yet shown benefits for sepsis patients. DIC is a dynamic process, and hypercoagulability is regarded as a hallmark of its early stages. However, assessment of this hypercoagulable state rely on tests that measure specific compartments of hemostasis, such as levels of anticoagulant proteins, fibrinogen and markers of fibrin degradation. Because hemostasis is a complex system, whether these assays actually depict the net result of interactions of all elements in the host is a fair concern. In fact, disconnection between classical assays and global assays of hemostasis is being demonstrated in patients with cirrhosis.

Here we performed laboratory evaluation of hemostasis in 24 patients with hematological malignancies and febrile neutropenia, in the early stages of sepsis. In addition to classical assays used in DIC such as platelet count (PC), fibrinogen (Fib), prothrombin time (PT) and D dimer (DD), thrombin generation (TG) was evaluated using a fluorogenic method (Technoclone, Vienna, Austria) in platelet poor plasma samples. Selection of patients with hematological malignancies and chemotherapy-induced neutropenia allowed us to obtain a baseline sample before the inititiation of chemotherapy, against which all comparisons were made. In addition, this strategy allowed us to obtain the 1^st sample within 12h from fever onset, thus standardizing the time of evaluation, a key variable in studies of coagulation in sepsis. Laboratory evaluation was repeated 48h after fever onset. A sepsis severity score (SOFA) was recorder daily.

Median age was 42 years-old (16–62). Baseline diagnosis included acute leukemias in 14 and other hematological malignancies in 10. At fever onset, mean neutrophil count was 125/ml (range 20–500). Sepsis was defined according do ACCP/SSCM criteria. SOFA score at fever onset and 48 hours thereafter were 3 (range 0–13) and 4 (range 1–12) respectively. The proportion of patients with overt DIC based on classical ISTH score was overestimated by the presence of severe thrombocytopenia. Using an arbitrary modification to correct for this factor, only 1 patient presented overt DIC. Septic shock developed in 8 patients, in a median of 4 days from fever onset. Classical parameters of coagulation behaved as expected for the early phases of sepsis: PT remained stable, Fib and DD increased progressively. PC analysis was hampered by severe myelotoxicity. Total TG, expressed by the area under the curve of the thrombin generation curve (AUC), peak thrombin and lag time were not changed at fever onset and 48 hours thereafter compared to baseline values, and to values obtained in healthy individuals. An increase in the time to peak thrombin generation and a decrease in the velocity index were the only significant changes observed in our study. A positive correlation was observed between the lag time to TG and the SOFA score, and a negative correlation was observed between the SOFA score and AUC at the time of fever onset (all r>0.5 with P<0.05). In an exploratory analysis of the association of TG parameters with septic shock development, no significant association was observed.

In a population of patients with hematological malignancies and febrile neutropenia, TG was not increased in the early stages of sepsis. Our analysis also suggests that the kinetics of TG might be changed in the early stages of sepsis, but towards a slower activation of coagulation. These results are in accordance with recently published papers that evaluated septic patients with whole blood thromboelastography. The prognostic value of TG parameters in sepsis deserves further studies since sample size our study was not powered to draw definite conclusions about this. No evidence of hypercoagulability in patients with early sepsis could be demonstrated in our study using a global hemostasis test.

No relevant conflicts of interest to declare.