The Reciprocal Relationship Between Inflammation and Coagulation

O'Brien, Mauria

doi:10.1053/j.tcam.2012.06.003

Cited by 73 publications

(68 citation statements)

References 106 publications

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“…In the wake of microbial penetrance, a number of pathways initiate thrombogenesis in tandem with the inflammatory response. 39 Controlled induction of thrombus formation within select vascular sites allows construction of a scaffolding network to ensnare microbial particles in a manner that parallels NETs. Although a thrombus is not traditionally considered a component of the immune response, evidence suggests that the clotting pathway activated in collaboration with inflammation is intended to serve a physiologic purpose.…”

Section: Platelets and The Immune Systemmentioning

confidence: 99%

Platelets at the interface of thrombosis, inflammation, and cancer

Franco

Corken

Ware

2015

Blood

533

453

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Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet’s origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet’s involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.

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Section: Platelets and The Immune Systemmentioning

confidence: 99%

Platelets at the interface of thrombosis, inflammation, and cancer

Franco

Corken

Ware

2015

Blood

533

453

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“…Results from our and other studies demonstrate the tight links between the regulation of the fibrinolytic system and the inflammatory response (5,45). We show here that in the absence of A2AP, the inflammatory response is enhanced during Y. pestis ⌬pla strain infection, suggesting a role for A2AP in regulating inflammation during Y. pestis infection, most likely through activities associated with plasmin(ogen).…”

Section: Discussionmentioning

confidence: 47%

Impact of the Pla Protease Substrate α2-Antiplasmin on the Progression of Primary Pneumonic Plague

et al. 2015

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Many pathogens usurp the host hemostatic system during infection to promote pathogenesis. Yersinia pestis, the causative agent of plague, expresses the plasminogen activator protease Pla, which has been shown in vitro to target and cleave multiple proteins within the fibrinolytic pathway, including the plasmin inhibitor ␣2-antiplasmin (A2AP). It is not known, however, if Pla inactivates A2AP in vivo; the role of A2AP during respiratory Y. pestis infection is not known either. Here, we show that Y. pestis does not appreciably cleave A2AP in a Pla-dependent manner in the lungs during experimental pneumonic plague. Furthermore, following intranasal infection with Y. pestis, A2AP-deficient mice exhibit no difference in survival time, bacterial burden in the lungs, or dissemination from wild-type mice. Instead, we found that in the absence of Pla, A2AP contributes to the control of the pulmonary inflammatory response during infection by reducing neutrophil recruitment and cytokine production, resulting in altered immunopathology of the lungs compared to A2AP-deficient mice. Thus, our data demonstrate that A2AP is not significantly affected by the Pla protease during pneumonic plague, and although A2AP participates in immune modulation in the lungs, it has limited impact on the course or ultimate outcome of the infection. The activation of coagulation, resulting in fibrin deposition and fibrin cross-linking, is a host mechanism to stop bleeding and to physically contain invading microorganisms (1, 2). Subsequently, mechanisms to induce fibrinolysis are activated via tightly regulated proteolytic cascades (3). During this phase, tissue-bound and secreted activators mediate the conversion of the circulating zymogen plasminogen into its active serine protease form, plasmin. In addition, the host innate immune system is tightly linked to the hemostatic system. By coordinating host platelet activation and aggregation, coagulation, fibrinolysis, and inflammation, the innate immune response can synchronize the sensing of invading pathogens, immune cell recruitment, and pathogen elimination, as well as subsequent tissue repair (3-5).As a part of the fibrinolytic system, plasmin degrades fibrin clots with additional biological activities related to tissue remodeling, cell migration, and inflammation (6). In addition, there exist endogenous inhibitors of both active plasmin and plasmin generation to maintain homeostasis. To control the generation of plasmin, plasminogen activator inhibitor 1 (PAI-1) inactivates the plasminogen activators urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) (7,8). On the other hand, ␣2-antiplasmin (A2AP) inhibits plasmin directly. A2AP is synthesized in the liver and maintained in the circulation to rapidly inhibit freely circulating active plasmin (9). Currently, the only known biological function of A2AP is to inhibit active plasmin; this occurs via a set of interaction steps, which culminates in the formation of an enzymatically inactive 1:1 stoichiometric complex of p...

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“…11 These conditions often result in extensive cross-talk that exists between inflammation and coagulation, with a potential final outcome of MODS and eventual death. 5,12 3. Coagulation cascades…”

Section: Sepsismentioning

confidence: 99%

Coagulation abnormalities in sepsis

Tsao

2015

Acta Anaesthesiologica Taiwanica

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Although the pathophysiology of sepsis has been elucidated with the passage of time, sepsis may be regarded as an uncontrolled inflammatory and procoagulant response to infection. The hemostatic changes in sepsis range from subclinical activation of blood coagulation to acute disseminated intravascular coagulation (DIC). DIC is characterized by widespread microvascular thrombosis, which contributes to multiple organ dysfunction/failure, and subsequent consumption of platelets and coagulation factors, eventually causing bleeding manifestations. The diagnosis of DIC can be made using routinely available laboratory tests, scoring algorithms, and thromboelastography. In this cascade of events, the inhibition of coagulation activation and platelet function is conjectured as a useful tool for attenuating inflammatory response and improving outcomes in sepsis. A number of clinical trials of anticoagulants were performed, but none of them have been recognized as a standard therapy because recombinant activated protein C was withdrawn from the market owing to its insufficient efficacy in a randomized controlled trial. However, these subgroup analyses of activated protein C, antithrombin, and thrombomodulin trials show that overt coagulation activation is strongly associated with the best therapeutic effect of the inhibitor. In addition, antiplatelet drugs, including acetylsalicylic acid, P2Y12 inhibitors, and glycoprotein IIb/IIIa antagonists, may reduce organ failure and mortality in the experimental model of sepsis without a concomitant increased bleeding risk, which should be supported by solid clinical data. For a state-of-the-art treatment of sepsis, the efficacy of anticoagulant and antiplatelet agents needs to be proved in further large-scale prospective, interventional, randomized validation trials.

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The Reciprocal Relationship Between Inflammation and Coagulation

Cited by 73 publications

References 106 publications

Platelets at the interface of thrombosis, inflammation, and cancer

Platelets at the interface of thrombosis, inflammation, and cancer

Impact of the Pla Protease Substrate α2-Antiplasmin on the Progression of Primary Pneumonic Plague

Coagulation abnormalities in sepsis

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