The cancer related thrombotic tendency in sepsis.

The host inflammatory response is activated in both cancer and infection. This includes enhanced production of acute phase reactants, involvement of coagulation and inflammation and the potential for systemic effects. This overview will identify the prothrombotic links between cancer and sepsis and suggest antithrombotic agents as an approach in the specific treatment of sepsis in cancer patients.

Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB.

OBJECTIVE: To review the anti-inflammatory and anti-apoptotic properties of drotrecogin alfa (activated) (recombinant human activated protein C), emphasizing its modulatory effects on endothelial nuclear factor-kappaB. We propose a broad anti-inflammatory effect of drotrecogin alfa (activated), acting on both endothelium and monocytes. DATA SOURCES: A selected review of the published literature on nuclear factor-kappaB, severe sepsis, and the use of drotrecogin alfa (activated) in clinical and preclinical models, together with data derived from preclinical gene profiling of model systems. DATA EXTRACTION AND SYNTHESIS: Data from the PROWESS trial support the preclinical evidence of an antithrombotic effect of drotrecogin alfa (activated). Anti-inflammatory effects through reduction of thrombin generation and through thrombin-independent mechanisms in mononuclear and endothelial cells are reviewed. Inhibition of apoptosis is used as an example of the protective effect of drotrecogin alfa (activated) on endothelial and mononuclear cell dysfunction. CONCLUSIONS: Drotrecogin alfa (activated) acts as a modulator of nuclear factor-kappaB to aid in the host immune response in endothelium and monocytes. Extrapolation of gene array findings to explain apoptosis in endothelium and monocytes, coupled with emerging preclinical reports, provides evidence to support the role of drotrecogin alfa (activated) in modulating nuclear factor-kappaB.

Leukocyte and endothelial cell interactions in sepsis: relevance of the protein C pathway.

OBJECTIVE: To give an overview of leukocyte and endothelial cell interactions in sepsis and to explore the role of the protein C pathway in modulating the innate immune response via its anti-inflammatory properties. DATA SOURCE: Novel in vitro data and a MEDLINE search for the terms "activated protein C," "recombinant human activated protein C," "inflammation," "leukocyte adhesion," and "sepsis" were used, along with clinical trial databases from the PROWESS trial and a phase I human endotoxin trial evaluating recombinant human activated protein C (drotrecogin alfa [activated]). DATA EXTRACTION AND SYNTHESIS: The protein C pathway is positioned at the interface between the endothelium and the leukocyte response of the innate immune system. Activated protein C (APC) possesses profibrinolytic, anti-inflammatory, and anti-apoptotic properties, acting as an endothelial cell and microvascular modulator in opposition to thrombin and the proinflammatory cytokines. Distribution of the receptor for APC, endothelial protein C receptor, was detected on effector cells of the innate immune response. This suggests a further role for the protein C pathway in regulating inflammation. In neutrophils and eosinophils, an endothelial protein C receptor-mediated APC response leads to reduced migration in response to cytokine gradients. Endothelial protein C receptor may also suppress the apoptotic response in monocytes and enhance the expression of the adhesion integrin CD11b in granulocytes. The microvascular, anti-inflammatory influence of APC in sepsis is supported by suppression of endothelial cell adhesion molecules and the ability of APC to protect the endothelium from inflammatory insult. CONCLUSIONS: The coordinated effects of the protein C pathway on the endothelium and the leukocyte response of the innate immune system are supported by potential restriction of endothelial protein C receptor expression to cells of the innate immune system and by suppression of adhesion molecule expression on the endothelium by APC. Reduced neutrophil migration in response to cytokines is also mediated by endothelial protein C receptor. Further clinical studies will be needed to define the intrinsic role of the protein C pathway in coordinating the innate immune response in endothelium-based inflammation.

Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis.

INTRODUCTION: Drotrecogin alfa (activated; recombinant activated protein C) was shown to reduce 28-day all-cause mortality in patients with severe sepsis and to have an acceptable safety profile in 1690 patients studied in the F1K-MC-EVAD (PROWESS) trial. We analyzed all available data on the safety of treatment with drotrecogin alfa (activated) in 2786 adult patients with severe sepsis enrolled in all phase 2 and 3 clinical trials, and in an estimated 3991 patients receiving the drug in commercial use. PATIENTS AND METHOD: Mortality and safety analyses were performed on all available data from adult severe sepsis patients enrolled in seven clinical trials as of 12 April 2002. Trial-specific safety data and spontaneously reported serious adverse events from commercial use were extracted from a pharmacovigilance database. RESULTS: The 28-day mortality rate for all adult patients who received active treatment in all clinical trials was 25.3% (704/2786). Serious bleeding events during the infusion period and 28-day study period occurred in 2.8% (79/2786) and 5.3% (148/2786) of patients, respectively. Of bleeding events during the infusion period, 43% (34/79) were procedure-related. Fatal serious bleeding events during the infusion period occurred in 0.4% (12/2786) of cases. Intracranial hemorrhage (ICH) events during the infusion period and 28-day study period occurred in 0.6% (16/2786) and 1.1% (32/2786) of patients, respectively. Ten out of the 16 ICH events occurring during the study drug infusion period were associated with severe thrombocytopenia (

Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia.

Sepsis is associated with systemic inflammation, coagulopathy, and disrupted protein C (PC) pathway function. The effect of prothrombotic polymorphism, factor V Leiden (Arg506Gln; FV Leiden), was examined in a large clinical trial (PROWESS) of severe sepsis and a mouse endotoxemia model. In PROWESS, 4.1% (n = 65) of patients were heterozygous FV Leiden (VL+/-) carriers. The 28-day mortality was lower in VL+/- (13.9%) than in non-FV Leiden (VL-/-; 27.9%) patients (P =.013). The mortality benefit of recombinant human activated PC (rhAPC) treatment was similar in VL+/- (placebo, 15.6%; rhAPC,12.1%) and VL-/- patients (placebo, 31.0%; rhAPC, 24.7%; interaction P =.981). VL+/- status did not appear to influence baseline biomarkers of coagulopathy and inflammation or disease severity, with the exception that vasopressor usage was less in VL+/- patients (46.2% versus 63.0%; P =.009). In a median lethal dose (40 mg/kg) endotoxin mouse model, VL+/- mice had lower mortality than wild-type mice (19% versus 57%; P =.008), whereas the mortality of homozygous (VL+/+) mice was almost identical to that of wild-type mice (65% versus 57%; P =.76). The findings suggest that FV Leiden constitutes a rare example of a balanced gene polymorphism that maintains the FV Leiden mutation in the general gene pool due to a survival advantage of VL+/- in severe sepsis.