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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the National Centre for Inherited Coagulation
Disorders, St James's Hospital and Trinity College, Dublin, Ireland.
Activated protein C (APC) is a natural anticoagulant that plays a
pivotal role in coagulation homeostasis. Severe inherited or acquired
deficiency results in a clinical syndrome called purpura fulminans. In
addition, APC also appears to have potent cytokine-modifying properties
and is protective in animal models of sepsis. The dual functional
properties of APC are particularly relevant to severe meningococcemia,
where acquired PC deficiency is accompanied by multiorgan failure and
purpura fulminans. The authors conducted an open-label prospective
study assessing the efficacy of PC replacement therapy in patients with
severe meningococcal septicemia, purpura fulminans, and multiorgan
failure. The morbidity and mortality were compared with predicted
morbidity using the Glasgow Meningococcal Septicemia Prognostic Score.
Thirty-six patients with a mean age of 12 years (range 3 months to 72 years) were enrolled in the study. The mean ± SD for plasma PC
was 18 ± 7 IU/mL. PC was significantly lower than antithrombin or
protein S and was also significantly lower than PC levels in a cohort
of patients who developed meningococcemia without multiorgan failure
and purpura fulminans. A total of 3 of 36 (8%) patients died, which
compares favorably with predicted mortality of 18 of 36 (50%).
Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the
hospital, in comparison with the predicted amputation rate of 11 of 33 (30%). In conclusion, PC replacement therapy in severe meningococcal
septicemia was associated with a reduction in predicted morbidity and
mortality. The beneficial effect of PC replacement may reflect both the
anticoagulant and anti-inflammatory properties of the PC pathway.
(Blood. 2000;96:3719-3724) Meningococcemia in association with purpura
fulminans and hemodynamic deterioration continues to have a mortality
rate in excess of 50%.1,2 In patients who survive the
acute phase of the severe illness, mutilating complications and
end-organ failure are common.1,2 Like other inflammatory
response syndromes, meningococcemia is associated with clinical and
laboratory evidence of disseminate intravascular coagulation (DIC).
However, the reduction in protein C (PC) activity is far more severe in
this particular sepsis syndrome than in other related
conditions.3-5 The precise reason circulating PC should
drop to a greater extent than either antithrombin (AT) or protein S
(PS) is not fully understood. What is known, however, is that in
meningococcemia there is a strong correlation between the severity of
the acquired PC deficiency, the extent of the thrombotic skin lesions,
and a negative clinical outcome.6,7
The PC anticoagulant mechanism functions in vivo to suppress thrombotic
phenomena. This pathway is activated in the microcirculation, where
activated PC (APC) is generated "on demand" from PC following the
binding of thrombin to the endothelial receptor
thrombomodulin.8 APC in collaboration with its cofactor,
PS, which circulates free or complexed with the complement regulatory
protein C4bBP (60%), inactivates 2 of the cofactors critical for
thrombin generation, factors Va and VIIIa, and at the same time
promotes fibrinolysis.8 A receptor for PC is located on
the vascular endothelium and is called the endothelial protein C
receptor (EPCR).9 EPCR augments PC activation on the
endothelium by bringing PC into close proximity to the
thrombin:thrombomodulin complex and is quickly up-regulated in response
to endotoxin, a response that appears to be mediated by thrombin
because it is blocked by hirudin thrombin inhibitor.10,11 These observations suggest that EPCR plays an important role in the
activation of PC and in the regulation of coagulation homeostasis, especially in response to endotoxin.
The activation of PC to APC represents an important host defense
mechanism against excessive fibrin formation, and when this pathway
fails, purpura fulminans ensues. This syndrome is characterized by DIC
and microvascular thrombosis in the dermis, which may ultimately result
in renal failure, skin necrosis, gangrene, and amputation. The 3 most
common clinical situations where purpura fulminans is seen are severe
meningococcal disease, homozygous PC or PS deficiency, and autoimmune
PS or PC deficiency.
In addition to its anticoagulant properties, the PC pathway appears to
negatively regulate a variety of proinflammatory mediators. APC is
protective in animal models of sepsis and down-regulates lipopolysacharide-induced tumor necrosis factor (TNF)- Recent case reports and one small series has suggested that PC
replacement therapy is associated with a reduction in morbidity and
mortality in patients with severe meningococcemia and purpura fulminans.18-20 We hypothesized that PC replacement in
meningococcemia would reverse purpura fulminans and at the same time
improve multiorgan failure associated with proinflammatory cytokine
production. We report the results of an open-label prospective study
assessing the efficacy of PC replacement therapy in patients with
severe meningococcal septicemia, purpura fulminans, and multiorgan failure.
Study subjects
Coagulation parameters were also measured in a control group of 23 consecutive patients (12 males; 11 females) who developed meningococcemia without multiorgan failure or purpura fulminans (group
II). The mean age ± SD of these patients was 8 ± 14 years (range 3 months to 72 years).
Ethical approval was obtained from the institutional review board.
Informed consent was provided according to the Declaration of Helsinki.
Protein C concentrate
Antithrombin concentrate AT concentrate (Atenativ, antithrombin III, Kiba Pharmacia, Stockholm, Sweden) was used in 2 patients who had AT levels below 0.30 IU/mL. The AT concentrate was heat treated and purified by affinity chromatography on heparin-Sepharose gel.Laboratory investigations Venous whole blood was collected into 0.109-mol/L sodium citrate (Sarstedt Monovette 9NC/3mL) tubes and the plasma separated by centrifugation at 3800g for 10 minutes. PC and PS were measured by clotting assays (Instrumentation Laboratory, Lexicon, MA). AT was measured by chromogenic assay (Instrumentation Laboratory, Milan, Italy). The reference ranges in our laboratory for PC, PS, and AT were 80 to 130 IU/mL, 80 to 140 IU/mL, and 70 to 120 IU/mL, respectively. D-dimers were measured by latex agglutination (Fibronsticon, Organon Teknika, Boxtel, The Netherlands), and a normal value was defined as less than 500 µg/mL. Fibrinogen was determined by Klauss method (Thromboscreen Pacific Haemostasis) with a reference range of 1.5 to 4 g/L. Plasminogen-activator inhibitor-1 (PAI-1) antigen was measured by bioimmunoassay (Chromolize PAI-1, Biopool International, Sweden). The reference range for this assay in our laboratory was 4 to 43 ng/mL.
A diagnosis of Neisseria meningitidis was made
in all patients by either peripheral blood polymerase chain reaction,
blood cultures, or skin scrappings.23 Plasma PC and AT
were significantly lower in patients who developed multiorgan failure
(group I) than in the cohort patients who had meningococcemia without
multiorgan failure or purpura fulminans (group II). The mean ± SD
for PC was 18 ± 7 IU/mL versus 41.6 ± 13.3 IU/mL,
P < .001; for AT, 53 ± 16 IU/mL versus 81 ± 20
IU/mL, P < .001; and for PS, 74.9 ± 18.8 IU/mL versus
87.4 ± 14.1 IU/mL, P = ns. In addition, plasma PC was
significantly reduced in comparison with AT and PS within both groups,
P < .01 (Figure 1). While
the reduction in PC in all patients was inversely proportional to the
concentration of D-dimers, it was still significantly reduced in
patients with a normal D-dimer assay (Figure
2). This suggests that the reduction in
PC does not solely reflect increased consumption. PAI-1 levels were
significantly higher in patients with severe meningococcemia (group I)
than those with milder disease (group II), 1222.9 ± 1319 ng/mL
versus 185 ± 296 ng/mL, P = .02 (Figure
3).
PC concentrate was commenced within 18 hours in 35 of 37 patients. The mean interval to commencement of PC was 12 hours (range 2 to 72). Nineteen patients underwent continuous venovenous hemodiafiltration, and 2 patients underwent peritoneal dialysis. Heparin was administered to 26 patients. The reason for not using heparin in the remaining patients was either physician preference or failure to correct the coagulation parameters prior to death. No patient who received heparin developed hemorrhagic complications. AT concentrate was administered to 2 patients in whom the AT level was below 30 IU/mL. Both patients made a full and uneventful recovery. The mean ± SD GMSPS was 12 ± 2, which predicted a mortality of 18 of 36 (50%).22 The actual mortality was 3 of 36 (8%). One patient died from cerebral edema secondary to meningoencephalopathy. One patient died within 1 hour of admission to the hospital from refractory hypotension. The remaining patient died from intracerebral hemorrhage. The PC and fibrinogen levels were undetectable at diagnosis in this patient, and hemorrhage occurred despite replacement therapy with PC concentrate, cryoprecipitate (2 units per 10 kg of body weight of cryoprecipitate), fresh frozen plasma 40 (mL/kg), and platelets (postplatelet count 90 × 109/L). The fibrinogen and PC levels were not measured after replacement therapy and before the intracerebral hemorrhage. This patient did not receive heparin because fibrinogen and platelet counts were below the threshold level at the time of death. One patient recovered but suffered irreversible brain damage. This most likely resulted from meningoencephalopathy or anoxic injury sustained during a prolonged cardiac arrest, which occurred at time of admission prior to PC replacement. No hemorrhage was identified on computed tomography scan of the brain. Four of the 33 patients who survived the acute phase of the illness required amputation (12%). This compares favorably with the predicted risk of amputation of 33% (11 of 33).7,22,24,25 Two of the patients who required amputation had nonviable limbs prior to the initiation of PC 48 and 72 hours after admission to the hospital. One of these patients also suffered an ischemic stroke. The amputation rate for patients treated within 24 hours of admission to the hospital was 2 of 31 (6.5%). In both cases, PC was commenced within 5 hours after hospital admission. One of the remaining 28 survivors underwent skin grafting, and another patient required chronic hemodialysis. A total of 26 of 36 (72%) of the patients fully recovered with no complications.
First described by Vieusseaux in 1805, invasive meningococcal disease is a worldwide public health problem.26 Localized outbreaks in Ireland, which has one of the highest incidences in Europe, continues to cause serious alarm as a result of the fulminant pattern of disease and higher incidence among children and adolescents. Several scoring systems have been used to predict mortality and morbidity for meningococcemia. We selected the GMSPS (Table 2, Table 3).21 This score contains several clinical values plus the base deficit, is quick and easy to perform in most clinical settings, and has been retrospectively validated.22 The GMSPS is an accepted scoring system for meningococcal disease and has been used in the recent evaluation of novel treatment strategies in this condition.27,28 In the initial series, a score above 8 predicted 100% mortality. More recent reports describe survival at higher scores, with a mortality of 30% and 50% for scores of 8 and 12, respectively.24 In addition, a score of 10 or greater appears to be associated with a 30% risk of amputation.24 The mean ± SD GMSPS in the patients who received PC concentrate was 12 ± 2, which predicted a mortality of 18 of 36 (50%). The actual mortality in this cohort was only 3 of 36 (8%). These patients were treated in 8 different hospitals and therefore do not reflect the experience of a single highly resourced center. Furthermore, the mortality is far lower than previous published data on cohorts of patients that included those with mild, moderate, and severe disease.1,2,6,7,29 It is unlikely that PC replacement had either a positive or negative impact on the outcome of the patient who died from cerebral edema secondary to meningoencephalopathy or the one who survived with the severe neurologic deficit presumed secondary to meningoencephalopathy or anoxic injury. In addition, PC replacement was ineffective in the patient who was premorbid on admission to the hospital, which suggests that this therapeutic option may fail to salvage patients who are in the terminal phase of the sepsis syndrome. Intracerebral hemorrhage has been previously reported in meningococcal infection.30-33 Although the mechanism for this complication is unclear, it is likely that the severe deficiency of fibrinogen was an important contributing factor in the patient in this study. The correction of PC to within the normal range would not normally be expected to increase the risk of bleeding. However, it is possible that PC replacement disturbed a finely balanced equilibrium between severe deficiencies of natural anticoagulants and procoagulant and thereby increased the risk of hemorrhage. We have demonstrated a lower than expected amputation rate of 4 of 33 (12%) in patients with severe meningococcemia and purpura fulminans. This compares favorably with previously published data where 30% to 50% of survivors with similar disease severity required amputations.7,22,25 Furthermore, 2 patients who required amputations already had nonviable limbs at the time of initiation of PC, 48 and 72 hours after admission to the hospital, resulting in an amputation rate for patients treated with PC within 24 hours of admission to the hospital of 2 of 31 (6.5%). These 2 cases demonstrate that early PC replacement may fail to prevent the morbidity associated with purpura fulminans. It is possible that this failure reflects the biological properties of PC, which primarily prevents clot formation rather than lyse established thrombi. However, it is likely that the absolute level of PC is not the sole arbiter in determining either the development of purpura fulminans or response to therapy. This is supported by the absence of purpura fulminans in patients with similar reduction in PC associated with inherited deficiency states.34,35 Furthermore, although patients with severe meningococcemia and purpura fulminans (group I, Figure 2.1) have significantly lower PC levels than those patients with milder disease (group II, Figure 2.1), there is considerable overlap between the 2 groups. Therefore, additional defects within the PC pathway may contribute both to the pathophysiology of purpura fulminans and the effectiveness of PC replacement. The function of the PC pathway in meningococcemia may be further
compromised by increased C4B binding protein36 resulting in
decreased free protein S or by a decreased endogenous activation of PC
due to down-regulation of endothelial thrombomodulin or EPCR. A
reduction in free PS has not been reported in severe meningococcal disease, and we only detected mild reduction in PS using a
clotting-based assay that should be sensitive to free PS. However, in
vitro studies have demonstrated that endotoxin down-regulates
endothelial thrombomodulin, and EPCR expression has been shown to be
reduced in biopsies taken from the purpuric skin lesions of patients
with meningococcemia.37,38 The possibility that patients
who develop purpura fulminans harbor an inherited thrombophilic
predisposition was recently investigated.39 The prevalence
of the genetic risk factors for thrombosis was found to be no higher
than expected on the basis of their prevalence in the general
population (PS deficiency, PC deficiency, AT deficiency, APC
resistance, factor V Leiden mutation). Other studies have looked at the
possible role of the fibrinolytic pathway in meningococcemia. PAI-1
levels appear to correlate with TNF- PC was reduced to a far greater extent than the other natural
anticoagulants, which is consistent with previously published data
(Figure 1) and suggests that it does not solely result from increased
consumption. This is supported by the fact that PC was reduced in some
patients despite the presence of a normal D-dimer assay (Figure 2).
Recent data suggest that TNF- There are always hazards in comparing a nonrandomized clinical trial with contemporary and historical controls. Nevertheless, these data suggest that PC replacement therapy reduces morbidity and mortality in severe meningococcal septicemia. Although PC is not the sole determinant of purpura fulminans, PC replacement therapy may provide a safe and effective means of correcting a critical component in the pathophysiology of this condition. In addition, the anti-inflammatory properties of the PC pathway may negatively regulate the host inflammatory response and improve multiorgan failure and survival. Further work is required to confirm the benefits of PC infusion in severe meningococcemia and to identify more effective treatment strategies for patients who fail to respond to replacement therapy.
Submitted June 12, 2000; accepted August 15, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Owen P. Smith, Consultant Paediatric Haematologist, National Centre for Inherited Coagulation Disorders, Department of Haematology, St James's Hospital, James's St, Dublin 8, Ireland; e-mail: osmith{at}stjames.ie.
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© 2000 by The American Society of Hematology.
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  S. Zeerleder, C. E. Hack, and W. A. Wuillemin Disseminated Intravascular Coagulation in Sepsis Chest, October 1, 2005; 128(4): 2864 - 2875. [Abstract] [Full Text] [PDF]
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J. I. Weitz, J. Hirsh, and M. M. Samama New Anticoagulant Drugs: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 265S - 286S. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
and
interleukin-1
production in monocytes.
