SAN ANTONIO, TX—Inflammation has long been known to be part of the body’s response to infection. Evidence is accumulating that coagulation is part of that response as well. William C. Aird, MD, believes that the coordinated interaction between coagulation and inflammation is the rationale for using anticoagulants during the treatment of sepsis. However, underappreciation of the complexity of this interaction may be the primary reason that clinical trials of anticoagulants in sepsis patients have produced negative or only small results.

“The host response to infection includes an elaborate array of cells and proteins, including monocytes, endothelial cells, platelets, and components of the coagulation and inflammation cascades,” explained Dr. Aird, Associate Professor of Medicine (Hematology) at Harvard Medical School in Boston, who spoke at the annual meeting of the Society of Critical Care Medicine in San Antonio.[1] All of these cells must be considered if therapy is to be effective.

The pathophysiology of sepsis includes activation of monocytes, platelets, and the local endothelium. The monocytes secrete cytokines and other inflammatory mediators, which, in a feedback loop, further activate the monocytes and endothelial cells. However, the monocytes can also express tissue factor, thereby setting off the extrinsic pathway of the coagulation cascade. The result, said Dr. Aird, is a shift in the hemostatic balance toward the procoagulant side.

In addition, various serum proteases in the clotting cascade, including thrombin, appear to promote a proinflammatory phenotype by activating receptors on endothelial cells and monocytes. Research also suggests that fibrin may help keep pathogens “glued” to the macrophage, thereby aiding phagocytosis.

Thus, by inhibiting thrombosis, fibrin formation, and also thrombin-mediated receptor signaling, anticoagulants such as heparin and antithrombin III interfere with inflammation, suggested Dr. Aird. That was, indeed, shown to occur in preclinical studies of heparin or hirudin for severe sepsis in baboons, but these agents failed to ameliorate the animals’ organ dysfunction or mortality rates. Results of phase III trials of antithrombin III and tissue factor pathway inhibitor also showed no effect on mortality in patients with severe sepsis.

In another phase III trial, activated protein C produced a 19% relative risk reduction in 28-day all-cause mortality among the severe sepsis patients.[2] Consistent with its proposed role as an anti-inflammatory agent, activated protein C also reduced the patients’ interleukin 6 and D-dimer levels. Such declines did not occur with placebo.

Yet, activated protein C is not the “magic bullet” that can break the inflammatory cascade in severe sepsis. Although the drug does offer some hope, said Dr. Aird, about one quarter of the patients who receive it still die. If activated protein C does provide some benefit, it may accomplish this “by casting a larger therapeutic net” than other anticoagulants do, he suggested. For example, preliminary data suggest that activated protein C may favorably alter blood pressure through mechanisms yet undiscovered.

The interaction of biological pathways in sepsis is far too intricate to identify any single therapeutic solution, Dr. Aird concluded. “As long as the complexity of the host response to infection remains outside our grasp, as it does today, the best hope of therapeutic advance [in severe sepsis] will be with broad-based targeting.”

PLATELETS LINKED TO INFLAMMATION

Aside from their usual role in hemostasis, platelets have other previously unrecognized abilities that closely link them to inflammation, Guy A. Zimmerman, MD, reported at the annual meeting of the Society of Critical Care Medicine.[1] The interaction between platelets and different leukocytes, such as neutrophils and monocytes, is an example of that link, noted Dr. Zimmerman, Director of the Program in Human Molecular Biology and Genetics at the University of Utah in Salt Lake City. This interaction can lead to platelet-leukocyte aggregation; such aggregation has been reported in sepsis, acute coronary syndromes, and other critical illnesses. In addition, “platelets themselves release and display on their surfaces a variety of inflammatory mediators,” Dr. Zimmerman explained; among those mediators are cytokines, such as interleukin 1b, and members of the CC and CXC chemokine family. “Degranulation and secretion of preformed mediators is a critical and rapid innate hemostatic and inflammatory response,” he suggested. While it is known that platelets carry messenger RNA despite their lack of nuclei, an important new finding shows platelets to be capable of signal-dependent translation of proteins. “In response to signals that are physiologically relevant in hemostasis and thrombosis, the platelet can translate some of the messenger RNA transcripts into the proteins that they code for,” Dr. Zimmerman said in an interview. That previously unrecognized ability can be detrimental in the presence of a pathologic process such as sepsis. “In such a situation, the platelets can be inappropriately signaled to make proteins that can then be used to fuel a pathologic thrombotic process,” he explained. This process can result in acute inflammation because one of the proteins, interleukin 1ß, is an inflammatory cytokine. In another important discovery, investigators have found that integrin alpha2b-ß3 regulates the translational responses of platelets. “This offers a potential therapeutic opportunity by interrupting signaling through those integrins,” Dr. Zimmerman said. His collaborators in these studies included Andrew S. Weyrich, PhD, and Stephan Lindemann, PhD, postdoctoral fellows.[2] —Timothy Begany

References 1. Zimmerman GA. Platelets: novel activities that link thrombosis to inflammation. Presented at: annual meeting of Society of Critical Care Medicine; February 1, 2003; San Antonio, Tex. 2. Lindemann S, Tolley ND, Dixon DA, et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1b synthesis. J Cell Biol. 2001;154:485-490.

—Timothy Begany

References
1. Aird WC. Coagulation and inflammation. Presented at: annual meeting of Society of Critical Care Medicine; February 1, 2003; San Antonio, Tex.
2. Ely EW, Laterre PF, Angus DC, et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med. 2003;31:12-19.

Return to table of contents