Kimberly Schlesinger, M.D., Hematology Fellow, University of Pittsburgh

Margaret Ragni, M.D., Director, Hemophilia Center of Western PA

INTRODUCTION

      New concepts are emerging on the relationship between coagulation, inflammatory, and sepsis pathways. These are based on studies of sepsis in humans and animal models of sepsis.

      Disseminated intravascular coagulation (DIC), previously considered a specific disease, is now considered part of a pathophysiologic process  involving excess coagulation such as seen in sepsis and related disorders, e.g. systemic inflammatory response syndrome (SIRS), or multi-organ dysfunction syndrome (MODS) (1-5).

      Although DIC was previously thought to result solely from activation of the coagulation system by endotoxin or tissue factor, new data suggest that the changes in DIC may also reflect the activation of pro-inflammatory cytokines. These same cytokines are part of the inflammatory response of sepsis.

      The purpose of this Update is to provide a concise summary of the relationship between coagulation, inflammation, sepsis, and DIC. The clinical and laboratory diagnosis of DIC, as well as new approaches to treatment will be discussed.

Sepsis: The Scope of the Problem

      As many as 500,000 individuals in the U.S. develop sepsis each year, rising with the aging population. Despite the best in antibiotic therapy and cardiopulmonary support, and the advances in our understanding of inflammation and coagulation in sepsis, as many as half these cases are fatal. The use of parenteral recombinant activated protein C (APC) was recently shown in a multi-center study (3) to significantly reduce mortality in some patients with severe sepsis. (See below).

      What is the role of APC in coagulation and in sepsis, and what is the relationship between the coagulation and inflammatory pathways?

Coagulation Pathways in Inflammation & Sepsis

      Activated protein C (APC) is a well-recognized  anti-thrombotic molecule. APC inactivates activated factors Va and VIIIa to limit and regulate clot formation. APC also promotes clot breakdown (fibrinolysis) by inhibiting plasminogen activator inhibitor (PAI-1).  APC also acts to limit the inflammatory response to infection, by inhibiting the continued production of  “pro-inflammatory” cytokines.  APC interferes with monocyte and neutrophil migration to sites of inflammatory, further limiting the propagation of the inflammatory response. Thus, regulation of both the coagulation cascade, limiting excess clot formation and inflammatory response highlight the role of APC in the septic response.

Cytokines in Sepsis and DIC

      During infection, inflammatory mediators are released and activated. These so-called “pro-inflammatory cytokines” include tumor necrosis factor (TNF-a), interleukin-1 (IL-1), and interleukin 6 (IL-6) (1,4, 5). Anti-inflammatory mediators, including IL-4 and IL-10, appear insufficient to regulate pro-inflammatory cytokines in severe sepsis.

      Prominent features of the septic response include uncontrolled inflammation and coagulation. Vascular endothelial damage is the triggering event, whether caused by endotoxin, tissue factor, necrotic cells, or amniotic fluid, becomes the triggering event. This endothelial damage leads to release of tissue factor, which activates the coagulation system resulting in excess thrombin generation. Subsequent clot formation promotes microvascular endothelial dysfunction, and, if unchecked, hypoxemia, organ dysfunction, and organ failure ensue.

      Endothelial damage and a shift towards a prothrombotic milieu lead to decreased expression and impaired function of endothelial receptors for thrombin, i.e. thrombomodulin, and protein C, i.e. the endothelial protein C receptor (EPCR) (2). Both thrombomodulin and EPCR are required for the conversion of protein C to its active form, APC. Thus, a major system for the regulation of thrombin formation, clot propagation, and protein C activation is lost (5).

      Nearly all patients with severe sepsis are deficient in protein C. Low protein C levels are associated with shock and poor outcomes, including ICU stay, ventilator dependence, and mortality (4).

Activated Protein C (APC) in Sepsis

      Over a decade ago, it was shown that APC protects against organ failure and death in a baboon model of sepsis (2). However, it was not until this year that the results of a multicenter, randomized, double-blind trial of adults with sepsis was reported by Bernard et al (3).

      A diagnosis of severe sepsis was strictly defined, including evidence of infection, systemic inflammation and organ dysfunction. Activated protein C (APC, Drotrecogin alfa, Xigris) was given as a 96-hour infusion, within 24 hours of diagnosis. Because of its anticoagulant effects, subjects were excluded for coagulopathy, thrombocytopenia < 30,000/ml, recent surgery, or heparin treatment.

      APC treatment was associated with a significant reduction in the pro-inflammatory cytokine IL-6 and in D-dimer, a marker of thrombin generation (3). These changes were associated with reduced sepsis-related mortality. Bleeding was the most common adverse event, primarily of the gastrointestinal tract.

Summary

      The results of this study of APC underscore the importance of the protein C pathway in sepsis, the inflammatory response, and sepsis-related coagulopathy.  Supplying APC exogenously in severe sepsis helps to restore regulation of inflammatory and coagulation responses in some patients, leading to a favorable survival benefit.

      Not all patients benefited from APC, however. It is possible, but unproven, that there is a finite time during which the inflammatory response associated with sepsis is reversible, and, presumably, during which treatment, if given early enough, could favorably affect the outcome. 

      Hopefully, further study will help define optimal APC use as well as lead to the development of other potent inhibitors of the inflammation to reduce sepsis, inflammation, and DIC mortality.

References:

1.  Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-92.

2.  Taylor BF, Chank A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of E.coli  infusion in the
     baboon. J Clin Invest 1987; 79: 918-25.

3.  Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis.
     N Engl J Med 2001; 344: 699- 709.

4.  Yan SB, Helterbrand J, Hartman DL, et al. Low levels of protein C are associated with poor outcome in severe sepsis.
     Chest 2001; 120: 915- 22.

5.  Kurosawa S, Stearns-Kurosawa DJ, Hidari N, Esmon CT. Identification of functional endothelial protein C receptor in human
     plasma. J Clin Invest   1997; 100: 411-18.