Sepsis is a prevalent cause of hospital mortality. Terminal complications of sepsis include hemorrhage and multi-organ failure due to consumption of platelets and coagulation factors into clots within microcirculation, condition termed disseminated intravascular coagulation (DIC). Platelets and coagulation factors play a vital role in hemostatic plug formation to staunch blood loss upon blood vessel barrier breach. A similar process can also lead to pathological thrombus formation and consequential thrombotic complications and potentially DIC. There is a pressing need for a better (patho)mechanistic understanding of thrombosis versus hemostasis, which could help guide therapeutic interventions to prevent DIC while preserving hemostasis in septic patients. Thrombosis and hemostasis appear to separate mechanistically upstream of coagulation factor XI (FXI), as FXI and coagulation factor IX (FIX) deficiency cause mild and severe hemophilia, respectively, but coagulation factor XII (FXII) deficiency is asymptomatic. FXI-deficient humans are largely protected from deep vein thrombosis and ischemic stroke. Furthermore, inhibition of FXI activation by activated FXII (FXIIa) improves survival in mice with peritoneal sepsis or listeriosis. Thus, FXI inhibition could help prevent the thrombotic complications of sepsis. My preliminary data show that FXI promotes platelet activation and consumption in the bloodstream distal to a thrombus formation. We have previously shown that inhibiting FXI activation by FXIIa attenuated inflammation while improving survival of mice with fecal peritonitis. These findings suggest that FXIa is a multifunctional enzyme involved in different aspects coagulation and cellular response pertinent to sepsis progression. I hypothesize that FXI contributes to DIC by amplifying thrombin generation and directly affecting platelet interactions and endothelial barrier functions under shear. The goal of the proposed training plan is to delineate the mechanisms by which FXI contributes to sepsis- induced thrombotic complications.
Specific Aim 1 will determine the role of FXI in platelet consumption under shear flow. These studies will determine whether the presence of bacterial wall components promotes thrombin generation and subsequent platelet consumption in the bloodstream in a FXI-dependent manner.
Specific Aim 2 will determine the role of FXI in endothelial barrier dysfunction. I will determine whether FXI activity contributes directly or indirectly to endothelial barrier leak and subendothelial compartment exposure to the bloodstream. Collectively, my research will help define the role of FXI in sepsis and may lead to target identification for new therapies to improve patient outcomes. The objective of this fellowship is to attain a highly integrative training that would allow me to reach the competency I need to realize the research aims outlined in this proposal and pursue my future goal of becoming an effective physician-scientist.
Sepsis is a systemic pathophysiological response to a fulminant infection associated with, among others, thrombin generation amplification, consumption of platelets and clotting factors and vascular leak. The coagulation factor XI (FXI) is activated in the presence of negatively charged molecules, such as microbial cell wall components, and has been shown to promote thrombin generation as well as interact directly with platelets and endothelial cells. My research project aims to characterize the role of the coagulation factor XI in thrombohemorrhagic complications associated with sepsis.
|Zilberman-Rudenko, Jevgenia; Sylman, Joanna L; Lakshmanan, Hari H S et al. (2017) Dynamics of blood flow and thrombus formation in a multi-bypass microfluidic ladder network. Cell Mol Bioeng 10:16-29|
|Zilberman-Rudenko, Jevgenia; Sylman, Joanna L; Garland, Kathleen S et al. (2017) Utility of microfluidic devices to study the platelet-endothelium interface. Platelets 28:449-456|
|Sylman, Joanna L; Daalkhaijav, Uranbileg; Zhang, Ying et al. (2017) Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin. Ann Biomed Eng 45:1328-1340|
|Zilberman-Rudenko, Jevgenia; McCarty, Owen J T (2017) Utility and development of microfluidic platforms for platelet research. Platelets 28:425-426|
|Deguchi, Hiroshi; Sinha, Ranjeet K; Marchese, Patrizia et al. (2016) Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va. Blood 128:1870-1878|