| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
Dr. Opal is Professor of Medicine, Brown University School of Medicine.
Correspondence to: Steven M. Opal, Infectious Disease Division, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860
In this issue of CHEST (see page 915), Yan and colleagues demonstrate that 90% of a population of 70 patients who met the standard clinical criteria for severe sepsis had significantly reduced protein C levels. These investigators examined plasma samples from patients at study entry from a multicenter sepsis trial (the ibuprofen study1 ) and repeated coagulation assays on plasma samples from patients 44 h after study entry. While low baseline levels of protein C portend an unfavorable outcome, the results at 44 h after study entry were more predictive of fatal outcome (p < 0.05). These results are consistent with a considerable body of literature attesting to the adverse prognostic significance of low protein C levels in patients with severe sepsis.2 3 4 In addition to a rather predictable "dose-response" relationship (lower protein C levels, higher mortality rate), this study and several other recent investigations have documented that the failure of low protein C levels to recover in septic patients is highly correlated with a poor prognosis.4
In the current investigation, protein C levels were significantly reduced even in those patients (9 of 10 patients) with normal global measures of coagulation activation, such as prothrombin time, partial thromboplastin time, platelet count, and fibrinogen levels. These results indicate that protein C measurement is a highly sensitive marker of coagulation activation and, more importantly, clinically evident severe sepsis. If these results can be replicated in a larger patient population, these results have important clinical implications for clinical trial design. If the vast majority of patients who meet standard clinical criteria for severe sepsis already have low protein C levels, does this obviate the need for actual measurement of protein C before initiating therapy for protein C deficiency? The answer to this question awaits the final answer from the recently completed phase III clinical trial of activated protein C in severe sepsis.5 6
It is worth reflecting on the recent history of sepsis research and clinical trials designed to improve the outcome of patients with severe sepsis. For the last 25 years, the main focus of research has been directed against elements of the host immune response to systemic infection. Coagulation activation has been relegated to secondary importance in the pathogenesis and treatment of sepsis. The coagulation activation was assumed to be an epiphenomenon of ongoing systemic inflammation. It was incorrectly expected that regulation of the disordered inflammatory response of sepsis would allow for passive correction of the coagulation abnormalities. It now appears the opposite may be more clinically relevant. Control of disordered coagulation is of primary importance, and the interactions of coagulation and inflammation are central to the pathophysiology of septic shock. Resolution of the systemic inflammatory response may follow therapeutic interventions to re-establish homeostasis of the coagulation and fibrinolytic system.6
A number of investigators have systematically dissected the intricate interactions between coagulation, inflammation, and the pathogenesis of sepsis. It is now quite clear that, at least in experimental models, repletion of acquired protein C deficiency in sepsis not only corrects the coagulation abnormality but results in a survival benefit.7 8 9 There are tantalizing hints that the same strategy may be true in clinical sepsis as well. Case reports of protein C infusion in patients with meningococcemia have revealed promising results.4 10 Results of a large phase III clinical trial in severe sepsis also support the value of activated protein C therapy in the treatment of severe sepsis.5
Protein C may be uniquely positioned to serve as an essential regulator
of the microcirculation in health and disease. Protein C undergoes
extensive posttranslational modification, including vitamin K-dependent
carboxylation of glutamic acid residues, hydroxylation of aspartic
acid, intramolecular cleavage with a single disulfide bridge, and four
N-linked glycosylation sites.2
11
All of these
modifications are essential for activity but are insufficient to
generate a functional serine protease that inhibits factors Va and
VIIIa.
Protein C is a zymogen (proenzyme) that necessitates activation by excision of 12 amino acids off the amino terminus of the heavy chain of protein C. This vital activation process is mediated by thrombin itself in association with an endothelial surface protein known as thrombomodulin. Thrombomodulin is concentrated only on capillary endothelial surfaces.12 Thus, activated protein C exists precisely in the optimal location within the microcirculation that limits procoagulant activity.13
Regrettably, tumor necrosis factor inhibits the expression of thrombomodulin, thereby limiting protein C activation during systemic inflammatory states.14 Tumor necrosis factor also reduces endothelial protein C receptor on endothelial surfaces, further limiting protein C activation. In this manner, pro-inflammatory cytokines may contribute to microvascular thrombosis, thrombin-mediated endothelial cell, platelet and neutrophil activation, and multiorgan dysfunction.15 16 17
In addition to its anticoagulant properties, activated protein C is distinguished from other antithrombotics by its profibrinolytic activity (inhibition of plasminogen activated inhibitor-1 and reduced activity of thrombin activatable fibrinolysis inhibitor)18 and significant anti-inflammatory activity (attenuation of leukocyte gene expression)19 and reduction of neutrophil-endothelial cell interactions.20 The clinical relevance of the latter two activities to improved outcome in sepsis is unclear at present but a focus of considerable basic research currently.
The results of Yan and colleagues add further evidence in support of the therapeutic rationale for protein C supplementation in severe human sepsis. Activated protein C may be the preferred method of replenishment of protein C levels in patients with severe sepsis. Results of the current phase III trial of activated protein C and subsequent clinical studies with this recombinant human protein should clarify the ultimate role of the protein C pathway in septic shock.
References
B (NF-B) and tumour necrosis factor 
(TNF-) production in the THP-1 monocytic cell line. Br J Haematol 110,130-134[CrossRef][ISI][Medline]This article has been cited by other articles:
|
|
 |
|
  J. G. Ganopolsky and F. J. Castellino A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model Am. J. Pathol., October 1, 2004; 165(4): 1433 - 1446. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
