Human recombinant activated protein C in meningococcal sepsis.

A 19-year-old woman presented with purpura fulminans and septic shock; subsequently, progressive coagulopathy, widespread purpura fulminans associated with meningococcemia, severe shock, respiratory, and renal failure developed. This clinical course was associated with depletion of functional protein C levels to < 5%. We describe her clinical course and therapy with human recombinant activated protein C.     

Recombinant factor VII (activated) for haemorrhagic complications of severe sepsis treated with recombinant protein C (activated)

We report on 2 cases of severe sepsis treated with drotrecogin-alpha (Xigris, Eli Lilly), where massive perioperative haemorrhage required administration of recombinant factor VIIa. The first patient developed severe sepsis after surgery (laparoscopic cholecystectomy, laparotomy due to peritonitis). After 18 h of treatment with Xigris, the patient developed massive, refractory gastrointestinal and abdominal bleeding. Effective haemostasis was achieved after 2 doses of NovoSeven (Novo Nordisk, Denmark). The patient died due to a cerebral bleed. The second patient developed septic shock in the course of pyelonephritis and right hydronephrosis. She was treated with Xigris and nephrectomy. Uncontrollable perioperative bleeding was effectively treated with 2 doses of NovoSeven. The patient survived.     

活化蛋白C治疗感染中毒症及其所致急性肺损伤的研究进展

近来的研究表明活化蛋白C（APC）在感染中毒症中具有抗凝、促纤溶和抗炎作用。重组人活化蛋白C（rhAPC）可显著降低感染中毒症患者的病死率。但rhAPC在临床应用中的适应证及其有效性仍存在争议。细胞学研究提示APC可通过与细胞表面受体结合,激活细胞内的各种蛋白酶,使其磷酸化或去磷酸化,诱导细胞内信号转导,调节炎症相关基因的表达,从而调节参与感染中毒症的多个重要病理生理过程。此外,APC可能对感染中毒症所致急性肺损伤起到保护性作用。     

Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis

Recombinant human activated protein C (rhAPC) is a natural anticoagulant with potentially important anti-inflammatory properties. In humans with severe sepsis, rhAPC treatment reduces mortality, but mechanisms responsible have not been well characterized. Accumulation of activated neutrophils in the lungs and other organs during severe infection contributes to sepsis-induced organ dysfunction, including acute inflammatory lung injury. Because neutrophils express an APC receptor, we hypothesized that immunomodulatory effects of rhAPC occur, in part, via modulation of neutrophil responses. To examine this issue, we performed a double-blinded, placebo-controlled study of rhAPC in a human model of endotoxin-induced pulmonary inflammation. Administration of rhAPC significantly reduced leukocyte accumulation to the airspaces, independent of pulmonary cytokine or chemokine release. Neutrophils recovered from bronchoalveolar lavage fluid of volunteers receiving rhAPC demonstrated decreased chemotaxis ex vivo. Decreased neutrophil chemotaxis following exposure to rhAPC was confirmed in vitro. No differences were detected in gene expression, kinase activation, cytokine release, cell survival, or apoptosis of neutrophils recovered in the presence or absence of rhAPC. These studies demonstrate that rhAPC reduces both endotoxin-induced accumulation of leukocytes in the airspaces and neutrophil chemotaxis. These rhAPC-induced effects on neutrophil function may represent a mechanism by which rhAPC improves survival in patients with sepsis.     

Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness

PURPOSE OF REVIEW: Dysregulation of endogenous coagulant and anticoagulant systems is now believed to play an important role in the pathogenesis of sepsis and septic shock. Reductions in host activated protein C levels and resultant microvascular thrombosis provided a basis for the use of recombinant human activated protein C in sepsis. Although controversial, the findings from an initial phase III trial testing this agent resulted in its approval for use in patients with severe sepsis and high risk of death. This review highlights emerging insights into the biology of protein C and activated protein C in sepsis, summarizes additional analysis growing out of the phase III trial testing recombinant human activated protein C, and assesses the cost-effectiveness that the clinical use of the agent has had thus far. RECENT FINDINGS: Binding of activated protein C to the endothelial cell protein C receptor is recognized to result in a growing number of actions including increased activity of activated protein C itself and inhibition of both nuclear factor-kappaB, a central regulator in the host inflammatory response, and apoptosis. Additional analysis of the original phase III trial testing recombinant human activated protein C appears to emphasize one of the US Food and Drug Administration's original concerns regarding an association between severity of sepsis and this agent's effects. Postmarketing analysis and growing experience with other anticoagulant agents and corticosteroids in sepsis raise questions regarding the ultimate cost-effectiveness of activated protein C. SUMMARY: The protein C pathway is important both to coagulant and inflammatory pathways during sepsis. Based on emerging investigations, its actions appear to be increasingly complex ones. Despite potentially promising results in an initial phase III trial, the role of recombinant human activated protein C in the treatment of septic patients must continue to be evaluated.     

Recombinant human activated protein C as a disease modifier in severe acute pancreatitis: Systematic review of current evidence

BackgroundThe severity of organ failure caused by acute pancreatitis (AP) is the most important determinant of mortality in the disease. Recombinant human activated protein C (Drotrecogin Alfa; Xigris, APC, rhAPC) is the first drug to show a decrease in all-cause mortality due to multiple organ failure caused by sepsis. As the systemic inflammatory response syndrome (SIRS) that causes organ failure in early AP is similar to that caused by severe sepsis, the use of rhAPC in the management of AP has been investigated in experimental and clinical studies which are collated in this review.MethodsA literature review of published material identified from MEDLINE and EMBASE databases, for the period from January 1985 to January 2011, reporting rhAPC usage in AP.Results3 of 4 experimental studies reported an improvement in outcome in animals with AP given rhAPC. The clinical randomized trial showed no improvement in outcome in the treatment arm.ConclusionThe experimental evidence of disease amelioration in AP following intervention with rhAPC has not translated to the small clinical RCT. Given that there were only 16 patients in the treatment arm, further clinical evaluation is justified.     

Recombinant factor VIIa: its background, development and clinical use

PURPOSE OF REVIEW: To examine the development of recombinant FVIIa (rFVIIa); a new concept of inducing hemostasis. It was developed for use in hemophilia patients with inhibitors against FVIII or FIX with the vision to provide these patients with a therapeutical option to be used instead of FVIII or FIX. For the first time it was shown that pharmacological doses of FVIIa induced hemostasis. RECENT FINDINGS: Hemostasis was achieved by rFVIIa in major surgery (repeated doses) as well as in a home-treatment setting (one single injection) in severe hemophilia patients with inhibitors. A recent study indicates that rFVIIa may be useful as prophylaxis. In heavily bleeding nonhemophilia patients rFVIIa was shown to induce hemostasis. Pharmacological doses of rFVIIa enhance thrombin generation on activated platelets resulting in the formation of tight hemostatic fibrin plugs resistant against premature proteolysis. High doses of rFVIIa seem to be safe probably due to its localized effect. SUMMARY: Pharmacological doses of rFVIIa induce hemostasis in severe hemophilia and in nonhemophilia patients with profuse, heavy bleeding. rFVIIa enhances thrombin generation on activated platelets, thereby initiating the formation of strong, tight fibrin hemostatic plugs resistant to premature lysis. It also seems to be safe in high doses.     

Guidance on patient identification and administration of recombinant human activated protein C for the treatment of severe sepsis

Approximately one-third of cases of severe sepsis result in death. Endogenous activated protein C (APC) plays a key role in the regulation of the inflammation, fibrinolysis and coagulation associated with severe sepsis. In a recently published phase III trial, Protein C Worldwide Evaluation in Severe Sepsis (PROWESS), intravenous administration of recombinant human APC (rhAPC) 24 μg/kg/h for 96 h to patients with severe sepsis resulted in a 6.1% reduction in absolute mortality and a 19.4% reduction in the relative risk of death from any cause within 28 days (number needed to treat = 16). This dose is now being applied in clinical practice.rhAPC is recommended for the treatment of severe sepsis (sepsis associated with acute organ dysfunction) occurring as a result of all types of infection (Gram-negative bacterial, Gram-positive bacterial and fungal). A panel of Canadian clinicians experienced in the treatment of severe sepsis and the management of critical care patients has developed this consensus document to assist clinicians in appropriate patient selection and management of potential challenges associated with rhAPC therapy.Key Words: Coagulation, Recombinant human activated protein C, Sepsis, Septic shock     

Patients with severe sepsis vary markedly in their ability to generate activated protein C

Activated protein C (APC) supplementation significantly reduces mortality in patients with severe sepsis, presumably by down-regulating coagulation, inflammation, and apoptosis. In vivo, endogenous APC is generated from protein C (PC) "on demand" in response to elevated thrombin levels. Thrombomodulin and endothelial cell protein C receptor are endothelial receptors required to generate APC endogenously. Since these receptors may be down-regulated in sepsis, we measured plasma markers of APC generation in 32 patients with severe sepsis to determine whether APC generation is impaired and whether markers of APC generation correlate with 28-day mortality. Relative to normals, all patients had elevated F1 + 2 and thrombin-antithrombin complex (TAT) levels (markers of thrombin generation and inhibition, respectively), and 28 of 32 patients had reduced PC levels. In 20 patients, APC levels paralleled elevated F1 + 2 levels, whereas 12 patients had low APC levels despite elevated F1 + 2 levels, suggesting that APC generation is impaired in the latter. No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores. Baseline APC levels were higher in survivors (P = .024), and baseline F1 + 2/APC ratios were lower in survivors (P = .047). Larger studies are warranted to establish whether APC generation profiles aid in managing sepsis.     

Human protein C and activated protein C Components of the human anticoagulation system

Protein C, the zymogen form of the anticoagulant protein, activated protein C, is a member of the vitamin K-dependent class of proteins that function in generation and control of formation of blood clots. This plasma protein consists of a series of domain regions that are qualitatively similar to those present in human coagulation factors VII, IX, and X, and that appear to be related to specific properties of these proteins. With the recent advent of rigorous application of genetic engineering strategies to this system, and the continuing discoveries and characterization of genotypes and phenotypes of protein C in patients, great progress has been made in understanding structure-function relationships of protein C and activated protein C. This review is a summary and synthesis of recent pertinent studies with an emphasis on these topics.     

Current role of activated protein C therapy for severe sepsis and septic shock

Drotrecogin alfa (activated) (DrotAA) has been approved for therapy of severe sepsis and septic shock for 7 years, but controversy persists regarding efficacy and safety. Only a single randomized, controlled trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; PROWESS) has shown evidence of efficacy, and the risk of complications (especially hemorrhage) is recognized. Moreover, subsequent prospective studies (albeit in children and lower-risk adult patient populations) have been nonconfirmatory. Opinion is polarized whether DrotAA is effective and should be used. Safety data are not in dispute (DrotAA therapy increases risk of bleeding complications), but controversy exists regarding efficacy, the ethics of marketing the drug, and the design and conduct of current and future trials designed to resolve efficacy questions. DrotAA is approved therapy in the United States, the European Union, and many other countries, and clinicians should keep the drug in their armamentarium, balancing risk and benefit, for therapy of patients with severe sepsis or septic shock who are at high risk of death until the controversy is resolved by randomized, prospective trials now in progress.     

Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V

Purified human factor VIII procoagulant protein (VIII:C) was treated with purified human activated protein C (APC) and the loss of VIII:C activity correlated with proteolysis of the VIII:C polypeptides. APC proteolyzed all VIII:C polypeptides with mol wt = 92,000 or greater, but not the doublet at mol wt = 79-80,000. These results and our previous thrombin activation studies of purified VIII:C, are analogous with similar studies of factor V and form the basis for the following hypothesis: activated VIII:C consists of heavy and light chain polypeptides [mol wt = 92,000 and mol wt = 79-80,000 (or 71-72,000), respectively] which are similar in Mr to the heavy and light chains of activated factor V. Thrombin activates VIII:C and V by generating these polypeptide chains from larger precursors and APC inactivates both molecules by cleavage at a site located in the heavy chain region of activated VIII:C and V.     

Guidance on patient identification and administration of recombinant human activated protein C for the treatment of severe sepsis.

Approximately one-third of cases of severe sepsis result in death. Endogenous activated protein C (APC) plays a key role in the regulation of the inflammation, fibrinolysis and coagulation associated with severe sepsis. In a recently published phase III trial, Protein C Worldwide Evaluation in Severe Sepsis (PROWESS), intravenous administration of recombinant human APC (rhAPC) 24 mug/kg/h for 96 h to patients with severe sepsis resulted in a 6.1% reduction in absolute mortality and a 19.4% reduction in the relative risk of death from any cause within 28 days (number needed to treat = 16). This dose is now being applied in clinical practice.rhAPC is recommended for the treatment of severe sepsis (sepsis associated with acute organ dysfunction) occurring as a result of all types of infection (Gram-negative bacterial, Gram-positive bacterial and fungal). A panel of Canadian clinicians experienced in the treatment of severe sepsis and the management of critical care patients has developed this consensus document to assist clinicians in appropriate patient selection and management of potential challenges associated with rhAPC therapy.     

Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation,fibrinolysis, and inflammation in acute human endotoxemia

Inflammatory and procoagulant host responses are closely related in sepsis. The protein C pathway serves as a regulatory pathway with anti-inflammatory and anticoagulant properties. Recently, recombinant human activated protein C (rhAPC) was shown to reduce mortality in severe sepsis. Nevertheless, the effects of rhAPC in humans are still ill defined. The infusion of low endotoxin doses into humans provides a standardized model to study inflammatory and hemostatic mechanisms. Thus, we investigated whether rhAPC acts as an anticoagulant or anti-inflammatory drug in human endotoxemia. There were 24 volunteers randomized to receive either 24 microg/kg per hour rhAPC or placebo intravenously for 8 hours. Lipopolysaccharide (LPS, 2 ng/kg) was administered 2 hours after starting the infusions. rhAPC decreased basal tissue factor (TF)-mRNA expression, and thrombin formation and action. In contrast, rhAPC did not significantly blunt LPS-induced thrombin generation. Consistently, rhAPC did not reduce LPS-induced levels of TF-mRNA or D-dimer and had no effect on fibrinolytic activity or inflammation. Finally, endogenous APC formation was enhanced during endotoxemia and appeared to be associated with inflammation rather than thrombin formation. In conclusion, even low-grade endotoxemia induces significant protein C activation. Infusion of rhAPC decreases "spontaneous" activation of coagulation but does not blunt LPS-induced, TF-mediated coagulation in healthy volunteers, which is in contrast to a number of anticoagulants.