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(Chest. 2002;121:292-295.)
© 2002 American College of Chest Physicians

Human Recombinant Activated Protein C in Meningococcal Sepsis*

Gregory Wcisel, MD; David Joyce, MD; Arna Gudmundsdottir, MD and D. Michael Shasby, MD, FCCP

* From the Department of Medicine, University of Iowa College of Medicine, Iowa City, IA.

Correspondence to: D. Michael Shasby, MD, FCCP, Department of Medicine, University of Iowa College of Medicine, Iowa City, IA 52242; e-mail: shasby{at}blue.weeg.uiowa.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Case Presentation
 Discussion
 References
 
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. (CHEST 2002; 121:292–295)

Key Words: human recombinant activated protein C • purpura fulminans • renal failure • respiratory failure • septic shock


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Case Presentation
 Discussion
 References
 
Sepsis is a complex syndrome caused by the response of the organism to infection. The precise pathogenesis of sepsis remains only partly defined, but many of its characteristics can be reproduced by the injection of cytokines into experimental animals. However, while some proinflammatory cytokines mimic some of the physiologic syndrome, it has become evident that the entire syndrome represents a complex balance of proinflammatory and anti-inflammatory cytokines, and that some of the participants are, almost certainly, yet undiscovered.1 2 3

While the precise pathogenesis of the entire sepsis paradigm is uncertain, portions of it are better understood. Endothelial intimal surfaces are affected by cytokines, with activation of ineffective clotting, which evolves into disseminated intravascular coagulation (DIC).4 Purpura fulminans, which is most often associated with meningococcemia, is a flagrant expression of sepsis-induced DIC, and is usually associated with profound shock, organ dysfunction, and high mortality. It presents clinically as retiform purpura, which histologically is a bland thrombosis of capillaries filled with fibrin. Prior reports5 6 of purpura fulminans in conjunction with meningococcemia have documented depletion of protein C, an important suppressor of thrombosis. Purpura fulminans also develops in patients with congenital protein C deficiency, and this disease responds to protein C supplementation.7 Smith et al8 extended the logic of this intervention, and successfully treated patients with meningococcus-induced purpura fulminans with protein C concentrate. In this article, we report the first case of purpura fulminans associated with meningococcemia treated with a human recombinant activated protein C.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Case Presentation
 Discussion
 References
 
Routine laboratory and coagulation studies were done in the clinical pathology laboratories of the University of Iowa Hospital. Recombinant human activated protein C was provided through a compassionate use protocol, LY203638, by Eli Lilly and Co. (Indianapolis, IN). This protocol was evaluated and approved by the University of Iowa Hospital Human Use Committee. Appropriate patient consent was obtained.


   Case Presentation
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 Abstract
 Introduction
 Materials and Methods
 Case Presentation
Discussion
 References
 
A 19-year-old female college student without a significant medical history presented with 2 weeks of sore throat, diarrhea, and intermittent fevers. Four days prior to hospital admission, she had a frontal headache with vomiting. The day prior to hospital admission, her symptoms had improved enough for her to attend classes. On the day of hospital admission, she awoke with diffuse myalgias and arthralgias and she noted "blotchy brown spots" on her legs. Her sexual history was noncontributory. She had no history of tobacco, alcohol, or drug abuse. Her temperature was 36.7°C, BP was 50/37 mm Hg, heart rate was 135 beats/min and regular, and respirations were 20 breaths/min with an O2 saturation of 98% on room air. She was alert but appeared acutely ill. Examination of her skin revealed a blotchy retiform purpuric rash on the lower extremities, trunk, and face. Some of the lesions on her lower extremities were > 2 cm in diameter. There was no meningismus, and she denied photophobia. The lungs were clear to auscultation, and heart sounds were normal. Pelvic and abdominal examination findings were unremarkable. Neurologic examination findings were normal, except for diffuse weakness.

The WBC count was 8,700/µL, hemoglobin was 11.5 g/dL, and platelet count was 101,000/µL. The creatinine level was 2.4 mg/dL (212 µM). The prothrombin time was 14 s, and the partial thromboplastin time (PTT) was 45 s. Fibrin degradation products were > 80. Functional protein C was 23%. Results of a portable chest radiograph were normal. A lumbar puncture was performed, and the cerebrospinal fluid contained 1 WBC and 18 RBCs. The cerebrospinal fluid protein level was 26 mg/dL, and the glucose level was 60 mg/dL (1,080 mM). No organisms were seen on Gram’s stain.

She received 2 g of ceftriaxone, 130 mg of gentamicin, and 1 g of vancomycin, and was admitted to the ICU. She also received 5.5 L of saline solution, 4 L of fresh frozen plasma (FFP), dopamine, and norepinephrine over the first 12 h to maintain a target mean arterial BP of 60 mmHg. Five hours after ICU admission, her oxygenation was worse, with a PaO2 of 49 mm Hg while receiving 85% oxygen by face mask. She was intubated, and mechanical ventilation was initiated. Her PaO2/fraction of inspired oxygen ratio was 52. A chest radiograph showed diffuse bilateral alveolar infiltrates. Her coagulation profile had also deteriorated. Her prothrombin time was 25 s, PTT was 73 s, and platelet count was 31,000/µL (Fig 1 ). Functional protein C was 5%. She received 4 U of FFP, and protein C increased to 15%. Ten hours after ICU admission, blood culture findings were positive for Gram-negative diplococci. Her APACHE (acute physiology and chronic health evaluation) II score during the first 24 h was 28.



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  		Figure 1.. Sequence of changes in platelets, international normalized ratio (INR), PTT, and functional protein C activity in the patient over the first 120 h. She received 2 U of FFP at 6 h and 8 h, and 4 U at 23 h. Infusion of recombinant activated protein C was started at 34 h (arrows) and continued for 96 h.

 
On the second day, the retiform purpura progressed and coalesced, involving more than half of her skin surface. A biopsy of the skin lesions showed thrombosis of superficial and deep vessels, mild inflammatory cell infiltrate, and focal extravasation of erythrocytes. Four more units of FFP were administered. Continuous venovenous hemofiltration was started for oliguric (urine output < 15 mL/h) renal failure (creatinine level, 4.4 mg/dL [389 µM]). While the cortisol level at ICU admission was 71 µg/dL (1,960 nM), the cortisol level on day 2 was 7.8 µg/dL (215 nM) and the response to synthetic adrenocorticotropic hormone was blunted. Treatment with dexamethasone was started.

Thirty-four hours after presentation, an infusion of recombinant activated protein C was started at 18 µg/kg/h and increased to 24 µg/kg/h after 30 min. This infusion was continued for 96 h. Figure 1 outlines the time course of her coagulopathy.

On the third day, the Gram-negative cocci in the blood cultures were identified as Neisseria meningitidis, group C, sensitive to penicillin, and antibiotics were changed to penicillin G. By the fourth day, oxygenation began to improve, and positive end-expiratory pressure was reduced to 10 cm H2O with a PaO2/fraction of inspired oxygen ratio of 237. On the fifth day, urine output increased to 30 mL/h and continuous venovenous hemofiltration was stopped. Her chest radiograph cleared, and she was extubated on the sixth day. She required dialysis for renal failure on days 6, 8, and 14, after which she regained adequate renal function. Subsequently, she developed acalculous cholecystitis that responded to drainage, and a severe postinfectious arthritis developed that responded to treatment with corticosteroids. Her skin lesions healed, and she required no grafts. She was transferred from the ICU to the ward on day 23, and she left the hospital alive on day 46.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Case Presentation
 Discussion
References
 
Our patient’s clinical course was fortunate. By many criteria, she had an expected mortality of > 90%. She met four of the five criteria of Stiehm and Damrosch,9 and three of five criteria were predictive up 90% mortality in their series. She had a Glascow meningococcal septicemia prognostic score of at least 9, which is predictive of mortality with a specificity of 95%.10 The level of protein C depletion is also a strong predictor of outcome in meningococcemia with purpura fulminans. Depletion of protein C to levels <= 5% has been associated with mortalities > 90%.8 11 12

Other more recent reports would also indicate that our patient had a high expected mortality. Nurnberger et al13 reported on the potential efficacy of hemostatic therapy (heparin, antithrombin, protein C concentrate, or FFP) in children with meningococcemia. They used the Neisseria sepsis index (NESI) to stratify the severity of illness in their patients. Of patients with NESI scores of 3 to 5, 90% of patients receiving hemostatic therapy survived while only 55% of patients not receiving hemostatic therapy survived. All of their patients with NESI scores of 6 to 8 died (five patients, four of whom received hemostatic therapy). They concluded that this therapy was probably not efficacious in this most seriously ill group. Our patient had a NESI of 7 to 8.

In another recent report, White et al14 compared children treated with protein C concentrate with historical control subjects. They also used the Glasgow meningococcal scoring system as an estimate of mortality, and observed a mortality of 8% in a cohort with a predicted mortality of 50%. This is similar to that observed by Nurnberger et al13 in the NESI 3 to 5 group. The Barcelona experience is another study15 that is a rich epidemiologic base for meningococcemia. Of the Barcelona patients with a hemorrhagic diathesis, the odds ratio for death was 63 (confidence interval, 20.7 to 194), and the observed mortality rate in this group was 60%.

Our patient’s functional protein C levels were rapidly depleted within a few hours of hospital admission, and she had a severe coagulopathy (Fig 1) . The coagulopathy responded partially to treatment with FFP, but functional protein C never was > 20% prior to initiating infusion of recombinant, activated protein C. This may reflect the amount of protein C available in the FFP, or it may reflect the effects of sepsis on activation of inactive protein C found in FFP.

Protein C is a serine protease and natural anticoagulant that binds endothelial surface thrombomodulin in the presence of excess thrombin to produce activated protein C.16 Activated protein C then interacts with protein S to inhibit factors Va and VIIIa and thereby limits thrombosis.17 In vitro, activated protein C also binds to a receptor on macrophages and inhibits tumor necrosis factor production.18 During sepsis-induced DIC, much of the protein C is complexed with inhibitors and cannot be activated.19 20 Sepsis may also inhibit the activity of thrombomodulin, which is necessary to activate protein C.21

Consumption of protein C in meningococcal purpura fulminans and other types of Gram-negative sepsis is well documented.11 12 20 22 Hereditary protein C deficiency manifests as purpura fulminans and responds to protein C concentrate.7 This is part of the rationale for using protein C concentrate in patients with purpura fulminans associated with meningococcemia. While there have not been large controlled trials of the efficacy of protein C in meningococcal purpura fulminans, the efficacy of protein C concentrate in those series8 11 13 14 in which it has been used is impressive when compared to historical control subjects.

Protein C concentrate contains inactive protein C that must be activated by the recipient’s microvasculature, and, as discussed above, this activation may be impaired in sepsis. The recombinant activated protein C we administered to our patient is activated when it is administered, and sepsis-derived inhibitors and decreased thrombomodulin activity do not affect its efficacy. The recombinant protein has also been reported22 to be more resistant to proteolysis by neutrophil elastase than native protein C. Hence, the recombinant activated protein C could potentially have more potency in meningococcal purpura fulminans than protein C concentrate, and it avoids the potential problems of blood product transmission of other diseases inherent in the concentrate preparations.

After this article was initially submitted, Bernard et al23 published a report of the efficacy of recombinant activated protein C in patients with severe sepsis. The observed efficacy (reduction of mortality from 31 to 25%) was not dependent on depletion of protein C, indicating that activated protein C affects the physiology of sepsis by mechanisms other than just restoring normal functional levels of an endogenous anticoagulant. However, the extreme depletion of protein C and the extensive microvascular thrombosis that is the essence of meningococcal purpura fulminans makes it very possible that repletion with activated protein C will have even greater efficacy in this setting than in sepsis from other causes. The efficacy of protein C concentrate in meningococcal purpura fulminans is consistent with this hypothesis.


   Acknowledgements
 
We thank Barbara Utterbach for determinations of resting protein C levels and activity.


   Footnotes
 
Abbreviations: DIC = disseminated intravascular coagulation; FFP = fresh frozen plasma; NESI = Neisseria sepsis index; PTT = partial thromboplastin time

Received for publication January 26, 2001. Accepted for publication June 20, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Case Presentation
 Discussion
 References
 

  1. Opal, SM (1998) Sepsis. Dale, DC Federman, DD eds. Scientific American medicine Scientific American New York, NY.
  2. Wang, H, Bloom, O, Zhang, M, et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285,248-251[Abstract/Free Full Text]
  3. Poltorak, A, He, X, Smirnova, I, et al (1998) Defective LPS signalling in C3H/HeJ and C57BL/10ScCr Mice: mutations in Tlr4 gene. Science 282,2085-2088[Abstract/Free Full Text]
  4. Levi, M, ten Cate, H, van der Poll, T, et al (1993) Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 270,975-979[Abstract]
  5. McGehee, WG, Rapaport, SI, Hijort, PF (1967) Intravascular coagulation in fulminant meningococcemia. Ann Intern Med 67,250-260
  6. Powers, DR, Larsen, R, Johnson, J, et al (1993) Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis 17,254-261[ISI][Medline]
  7. Dreyfus, M, Magny, F, Bridely, JF, et al (1991) Treatment of homozygous protein C deficiency and neonatal purpura fulminans with protein C concentrate. N Engl J Med 325,1565-1568[ISI][Medline]
  8. Smith, OP, White, B, Vaughan, D, et al (1997) Use of protein C concentrate, heparin, and haemodialfiltration in meningococcus-induced purpura fulminans. Lancet 350,1590-1593[CrossRef][ISI][Medline]
  9. Stiehm, ER, Damrosch, DS (1966) Factors in the prognosis of meningococcal infection. J Pediatr 68,457-462[CrossRef][ISI][Medline]
  10. Thomson, APJ, Sills, JA, Hart, CA (1991) Validation of the Glascow Meningococcal Septicemia Prognostic Score: a 10-year retrospective survey. Crit Care Med 19,26-30[ISI][Medline]
  11. Fijnvandraat, K, Derkx, B, Peters, M, et al (1995) Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 73,15-20[ISI][Medline]
  12. Fourrier, F, Chopin, C, Goudermand, J, et al (1992) Septic shock, multiple organ failure and disseminated intravascular coagulation: compared patterns of antithrombin III, protein C and protein S deficiencies. Chest 101,816-823[Abstract/Free Full Text]
  13. Nurnberger, W, Kries, R, Bohm, O, et al (1999) Systemic meningococcal infection: which children may benefit from adjuvant haemostatic therapy? Results from an observational study. Eur J Pediatr 158(suppl 3),S192-S196
  14. White, B, Livingstone, W, Murphy, C, et al (2000) An open-label study of hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 96,3719-3724[Abstract/Free Full Text]
  15. Barquet, N, Domingo, P, Cayla, J, et al (1999) Meningococcal disease in a large urban population (Barcelona, 1987–1992). Arch Intern Med 159,2329-2340[Abstract/Free Full Text]
  16. Esmon, CT, Fukudome, K (1995) Cellular regulation of the protein C pathway. Semin Cell Biol 6,259-268[ISI][Medline]
  17. Esmon, CT (1989) The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 264,4743-4746[Free Full Text]
  18. Gray, ST, Tsuchida, A, Hau, H, et al (1994) Selective inhibitory effects of the anticoagulant activated protein C on the response of human mononuclear phagocytes to LPS, INF {gamma}, or phorbol ester. J Immunol 153,3664-3668[Abstract]
  19. Marlar, RA, Endress-Brooks, J, Miller, C (1985) Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation. Blood 66,59-63[Abstract/Free Full Text]
  20. Scully, MF, Toh, CH, Hooggendoorn, H, et al (1993) Activation of protein C and its distribution between its inhibitors, protein C inhibitor, {alpha}1-anti-trypsin and {alpha}2-macroglobulin, in patients with disseminated intravascular coagulation. Thromb Haemost 69,448-453[ISI][Medline]
  21. Moore, KL, Esmon, CT, Esmon, NL (1989) Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood , 73,159-165[Abstract/Free Full Text]
  22. Philapitsch, A, Schwarz, HP (1993) The effect of leukocyte elastase on protein C and activated protein C [abstract]. Thromb Haemost 69,A664
  23. Bernard, G, Vincent, J-L, Laterre, P-F, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344,699-709[Abstract/Free Full Text]




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