Protein C substitution in sepsis-associated purpura fulminans

OBJECTIVE: To assess the effect of protein C (PC) substitution on imminent peripheral necroses and overall outcome in patients with sepsis-associated purpura fulminans. DESIGN: Case series. SETTING: Intensive care units of two university hospitals. PATIENTS: A total of 12 patients with purpura fulminans, disseminated intravascular coagulation and imminent peripheral necroses in association with sepsis caused by Neisseria meningitidis (n = 5), Streptococcus pneumoniae (n = 2), Capnocytophaga canimorsus (n = 2), and Staphylococcus aureus (n = 1). In two patients, no pathogens were identified. INTERVENTIONS: Intravenous administration of PC concentrate (100 IU/kg every 6 hrs). In addition, antithrombin III substitution, antimicrobial therapy, hemodynamic support, and mechanical ventilation in all patients and hemodiafiltration in 10 patients. MAIN RESULTS: After the onset of PC, progressive peripheral ischemia was reversed irrespective of the etiology of infection. Laboratory variables reflecting disseminated intravascular coagulation improved rapidly, although the recovery of the platelet count was retarded in the patients who subsequently died. No drug-related adverse events were noted. Amputations were necessary in two patients, and necrotic tips of fingers and toes were macerated in a third. The hospital mortality was 42%. Of the five lethal cases, two were caused by S. pneumoniae, one by N. meningitidis, one by C. canimorsus, and one by an unknown pathogen. CONCLUSIONS: This article provides encouraging results on the use of PC substitution in meningococcal purpura and presents new data on the administration of this drug to patients with septic purpura caused by other bacterial species. By clinical judgment, PC limited the extent of tissue necrosis. The small number of patients does not allow for any conclusions on the potential effect of PC on mortality. A controlled and randomized study with a larger number of patients is needed before any recommendations can be given on the use of PC in sepsis-related purpura fulminans and shock.     

Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study

PURPOSE: To document in patients with meningococcal purpura fulminans (PF), the effects of a combined supplementation with antithrombin (AT) and protein C (PC) plasma concentrates and to estimate the pharmacokinetics and dose requirements of each inhibitor. DESIGN: Retrospective study of 15 patients. SETTING. One paediatric and one adult ICU in a university hospital. INTERVENTIONS: In addition to standard intensive care, all patients received a 100 IU/kg loading dose of AT and PC concentrates, followed by a continuous infusion (AT: 100-150 IU.kg.day; PC: 100 IU.kg.day in adults, and 400 IU/kg in infants). MEASUREMENTS: Clinical data, coagulation, and fibrinolysis parameters, AT and PC activities, and free protein S (PS) levels were sequentially measured. Restitution ratio, median increment after supplementation, and half-life of clearance from plasma were calculated for the two plasma substitutes. RESULTS. At admission, all patients had a severe decrease in AT, PC, and PS levels. The supplementation regimen induced a substantial increase in AT and PC activities, peaking at H18 and H48, respectively. The supplementation procedure did not modify free PS levels. The median values of AT and PC restitution ratio, increment in plasma activity observed after 100 IU/kg concentrate, and apparent half-life of clearance from plasma were 0.85 U.ml.U.kg and 0.59 U.ml.U.kg, 23% and 21%, 16 h and 6 h, respectively. CONCLUSION: If AT and PC concentrates are to be given in fulminant meningococcemia, the doses of supplementation should be at least 150 IU/kg AT and 250 IU/kg PC as loading dose and 150 IU/kg AT and 200 IU/kg PC as daily maintenance therapy. Taking into account the individual variability in inhibitor deficiency and restitution ratio, repeated measurements of plasma levels are mandatory to obtain a patient-based adjustment of the supplementation.     

Sepsis-associated purpura fulminans in adults

Sepsis-associated purpura fulminans is defined as septicemia, shock, disseminated intravascular coagulation and circulatory failure leading to multiple organ dysfunction. 40-70% of patients with sepsis-associated purpura fulminans die. Early prognostic factors in adults have not been well delineated yet. Aim of our study was 1) to evaluate currently used scoring systems for meningococcal septicemia in the setting of sepsis-associated purpura fulminans and 2) to assess if other parameters are feasible as early prognostic factors. From 1.1 1994-31.12.1998 twelve patients (female: 7; mean age: 31 (21; 43) years) were studied. Six patients (50%) died within 2 hours and 7 days after admission despite standard intensive treatment. On admission non-survivors had a more pronounced degree of disseminated intravascular coagulation compared to survivors (platelet count 18000 (15000; 45000) G/l vs. 119.000 (111000; 152000) G/l, (p = 0.03); fibrinogen 67 (50; 108) mg/dl vs. 356 (234; 483) mg/dl, (p = 0.02); PTZ 28% (20%; 30%) vs. 44% (35%; 51%), (p = 0.05); aPTT 120 (120; 128) sec vs. 46 (44; 69) sec, (p = 0.001). Severity of lactic acidosis was significantly higher in non-survivors than in survivors (pH 7.08 (6.92; 7.21) vs. pH 7.4 (7.25; 7.4), (p = 0.02); lactate 13.5 (11; 15) mval/l vs. 6.0 (4.4; 6) mval/l, (p = 0.02); data presented as median (25-75% interquartile range). In our patients the Glasgow Meningococcal Septicemia Prognostic Score (GMSPS) and the Niklasson-Score failed to distinguish between survivors and non-survivors (GMSPS 7 (6; 11) vs 7.5 (7; 9) out of 15; predicted mortality according to Niklasson-Score 73% vs 88%). There was no difference in the APACHE II Score (22 (18.5, 24) vs 22 (20.25, 26)). The severity of disseminated intravascular coagulation assessed by routine laboratory parameters and the degree of lactic acidosis on admission were the strongest predictors of outcome in patients with sepsis-associated purpura fulminans. Scoring systems developed for patients with meningococcal septicemia are of limited value in the setting of sepsis-associated purpura fulminans.     

Rapid recovery of acquired purpura fulminans in a patient with familial C4bBP deficiency

A 32-year-old pregnant woman developed meningococcemia associated purpura fulminans and quickly improved with therapy. After this disease C4b-Binding Protein (C4bBP) plasma levels remained very low while protein S activity was in the normal range. Familial investigation proved a hereditary C4bBP deficiency. This observation points out the role of the protein C-protein S system during acquired purpura fulminans.     

Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized,double-blinded,placebo-controlled,dose-finding study

BACKGROUND: Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome. We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate. This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial. METHODS: Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days. Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points. All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products. RESULTS: Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered. Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs. APC normalized significantly faster with increasing dosages of protein C concentrate. No adverse reactions related to protein C concentrate were observed. Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups. Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes. CONCLUSIONS: Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.     

Severe bleeding symptoms in refractory idiopathic thrombocytopenic purpura: a case successfully treated with melatonin

The prognosis of patients with idiopathic thrombocytopenic purpura refractory to corticosteroids and splenectomy (refractory ITP) is poor; these patients present high morbidity from disease and its treatment and have a mortality rate of approximately 16%. A patient is reported with severe bleeding symptoms related to refractory ITP successfully treated with melatonin.     

Myocardial injury in meningococcus-induced purpura fulminans in children

OBJECTIVES: To assess the incidence of myocardial ischemia in meningococcus-induced purpura fulminans in pediatric patients, to compare troponin I (cTnI) levels with changes in electrocardiogram (ECG) and to evaluate whether cTnI is related to myocardial function and contractility, to severe acquired anticoagulant deficiency and to the severity of disease. METHODS: Twenty-two patients with acute meningococcemia, supported with inotropes or vasoactive agents, were studied, Blood samples for the determination of serum cTnI and conventional myocardial ischemia and coagulopathy markers were drawn daily. Measurements of cardiac index (CI), ejection (EF) and shortening fractions (SF) and ECGs were performed daily. RESULTS: The Leclerc score, the Neisseria sepsis index (NESI) and the pediatric risk of mortality (PRISM) score predicted a mean mortality rate of 34%, 27% and 23%, respectively. Four patients died (18%). Five patients (23 %) presented with myocardial ischemia. Their ECG ischemic changes were associated with pathologically high cTnI levels (1.93 +/- 0.13 vs 0.18 +/- 0.08 ng/ml, p < 0.001 for patients with or without ischemic changes) and depressed myocardial contractility (mean difference +/- SE -14 +/- 5%, p = 0.01, for the EF and -7.4 +/- 3, p < 0.02, for the SF). High cTnI values were significantly correlated to low protein C (PC) (p < 0.0001), factor VIII (p < 0.04) and antithrombin III (AIII, p = 0.01) levels, but not to the PRISM, Leclerc or the NESI scores. Means of AIII, VII, and especially of VIII, and PC, were significantly lower in ischemic than in non-ischemic patients, although severity scoring systems and inotropic support did not differ between the two groups. Survivors tended to significantly higher PC (p < 0.01) and factor VIII levels (p = 0.001) than non-survivors and, also, to lower levels of cTnI (p = 0.05) and CPK-MB (p < 0.05), while in meningococcal shock. CONCLUSIONS: The incidence of myocardial ischemia is increased in acute meningococcemia in pediatric patients and correlates with myocardial dysfunction. High cTnI is associated with severe coagulopathy, but not with clinical prognostic scores or inotropic support. Early recognition of myocardial injury, myocardial support and early replacement therapy with PC, AIII, factor VIII or fibrinogen might improve outcome in acute meningococcemia in children.     

急性感染性暴发性紫癜的诊断和治疗

暴发性紫癜(purpura fulminans,PF)是一种少见的快速进展性血栓栓塞性疾病,常伴有皮肤出血和弥散性血管内凝血(disseminated intravascular coagulation,DIC),可发展为多器官功能衰竭和大血管栓塞,病死率高达18％ ～40％[1].临床常见三种类型:①遗传性蛋白C、蛋白S缺乏或称为遗传性暴发性紫癜;②自身免疫获得性蛋白C、蛋白S缺乏,或称为特发性暴发性紫癜;③急性感染性暴发性紫癜(acute infectious purpura fulminans,AIRF).其中AIRF常因严重脓毒症、脓毒性休克收住ICU.早期诊断、恰当的治疗可改善预后.本文结合,郑州大学第一附属医院收治的一例AIRF,探讨该病的诊断与治疗,以提高对该病的认识.     

Electrolyte changes caused by hydrotherapy in purpura fulminans

Purpura fulminans is a rare manifestation of meningococcemia that in its full-blown form has a predictive death value of 61%. Those patients who survive usually develop gangrenous lesions that involve skin and underlying structures, mostly of the extremities and sometimes of the cheeks. Experience with early excision and skin grafting of these lesions has generally been unsatisfactory since, due to the unique pathophysiology of the disease and involvement of the most distal branches of the cutaneous circulation, the lesions are not completely demarcated until well after complete recovery from the acute phase of the disease. Recently there was an outburst of purpura fulminans in Southern California and other parts of the country. During the months of January and February 1986 we were consulted on five cases. These ranged from two months to six years in age and consisted of two boys and three girls. One two-month-old died during the acute phase, another six-year-old remained in shock and in need of hemodynamic and respiratory support and succumbed three weeks after the onset of the disease, during which time all four extremities showed progressive necrosis. Of the three patients that survived, one three-year-old girl resolved her purpuric lesions except for small necrotic patches on the buttocks that did not require surgical intervention. The other two children were left with gangrenous lesions of the upper and lower extremities over 30% of total body surface area. One of these two patients demonstrated an electrolyte disturbance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients

Introduction  

Purpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels.     

Current management of purpura fulminans: a multicenter study

Seven burn centers performed a 10-yr retrospective chart review of patients diagnosed with purpura fulminans. Patient demographics, etiology, presentation, medical and surgical treatment, and outcome were reviewed. A total of 70 patients were identified. Mean patient age was 13 yr. Neisseria meningitidis was the most common etiologic agent in infants and adolescents whereas Streptococcus commonly afflicted the adult population. Acute management consisted of antibiotic administration, volume resuscitation, ventilatory and inotropic support, with occasional use of corticosteroids (38%) and protein C replacement (9%). Full-thickness skin and soft-tissue necrosis was extensive, requiring skin grafting and amputations in 90% of the patients. One fourth of the patients required amputations of all extremities. Fasciotomies when performed early appeared to limit the level of amputation in 6 of 14 patients. Therefore, fasciotomies during the initial management of these patients may reduce the depth of soft-tissue involvement and the extent of amputations.