New plasma protein C and protein S concentrate: A synergy for therapeutic purposes.

BACKGROUND AND OBJECTIVES: Deficiencies of protein C (PC) or protein S (PS) are rare diseases, characterized by mutations in the PC or PS genes, which encode plasma serine proteases with anti-coagulant activity. Severe PC or PS deficiencies manifest in early life as neonatal purpura fulminans, a life-threatening heamorrhagic condition requiring immediate treatment. First-line treatment involves replacement therapy, followed by maintenance with anti-coagulants. Replacement therapy with specific protein concentrates is currently only limited to PC, and therefore, a PC + PS concentrate represents a useful addition to therapeutic options, particularly for severe PS deficiency. Further, the production of a PC + PS concentrate from unused plasma fractionation intermediates would impact favourably on manufacturing costs, and consequently therapy prices for patients and health systems. MATERIALS AND METHODS: Several chromatographic runs were performed on the same unused plasma fractionation intermediates using different supports to obtain a PC/PS concentrate. The best chromatographic mediums were chosen, in terms of specific activity and recovery. A full process of purification including virus inactivation/removal and lyophilization steps was set up. RESULTS: The final freeze-dried product had a mean PC concentration of 47.75 IU/mL with 11% of PS, and a mean specific activity of 202.5 IU/mg protein, corresponding to over 12,000-fold purification from plasma. CONCLUSION: The development of a novel concentrated PC/PS mixture obtained from a waste fraction of other commercial products could be used for its potential therapeutic role in the management of neonatal purpura fulminans pathology.

Efficacy of extended microthrombolysis in an elderly lady with purpura fulminans.

Purpura fulminans is a thrombotic emergency affecting small vessels of skin and of internal organs that may rapidly progress into necrotizing fasciitis, critical limb ischaemia and multiorgan failure; it often develops during an infection or as a postinfective 'autoimmune' disorder. Although supportive care and hydration are important, anticoagulation ought to be started to prevent further occlusions alongside blood products according to need. Herein, we describe the case of an elderly woman who received extended intravenous low-dose recombinant tissue plasminogen activator at the onset of purpura fulminans that salvaged her skin and prevented the development of multiorgan failure.

Clinical and genetic features of Chinese pediatric patients with severe congenital protein C deficiency who first presented with purpura fulminans: A case series study and literature review.

INTRODUCTION: Purpura fulminans (PF) is a hematological emergency that can be caused by severe congenital protein C (PC) deficiency. It has been rarely reported in the Chinese population. We aimed to characterize the clinical and genetic features of Chinese pediatric patients with severe congenital PC deficiency who first presented with PF. MATERIALS AND METHODS: Twelve pediatric patients were diagnosed with severe congenital PC deficiency with PF, which was diagnosed based on our hospital records and previous reports from 1988 to July 2021 in China. We evaluated the clinical and genetic features of these patients. RESULTS: Nine patients (9/12, 75%) had onsets that were observed within the first 48 h after birth. Six patients had a family history of thromboembolism. There was no consanguinity. Other symptoms were intracranial thrombosis or hemorrhage (4, 33.3%), ocular lesions (2, 16.7%), gastrointestinal hemorrhage (2, 16.7%) and kidney infarction before birth (1, 8.3%). All but one of the patients (one case not detected) had a plasma PC activity of <10%. The genetic study indicated that in the eight patients with inherited PC deficiency, two were homozygous, five were compound heterozygous and one was heterozygous for PC deficiency. CONCLUSION: This is the first and largest case series of Chinese pediatric patients with severe congenital PC deficiency who first presented with PF. It has been shown that treatment with both fresh frozen plasma and anticoagulants is recommended when PC concentrate is not easily available, especially in developing countries.

Meningococcus, this famous unknown.

Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Since the first description of the epidemic nature of the illness at the dawn of the nineteenth century, the scientific knowledge of meningococcal infection has increased greatly. Major advances have been made in the management of the disease with the advent of antimicrobial therapy and the implementation of meningococcal vaccines. More recently, an extensive knowledge has been accumulated on meningococcal interaction with its human host, revealing key processes involved in disease progression and new promising therapeutic approaches.

Neisseria meningitidis (méningocoque) est une bactérie à Gram négatif responsable de deux formes gravissimes de maladies invasives : le purpura fulminans et la méningite. Depuis la première description du caractère épidémique de la maladie à l'aube du 19e siècle, les connaissances scientifiques sur les infections méningococciques ont considérablement augmenté. Des progrès majeurs ont été réalisés dans la gestion de la maladie avec l'avènement des agents antimicrobiens et le développement de vaccins contre le méningocoque. De nombreuses connaissances ont récemment été accumulées sur son interaction avec l'être humain, son unique hôte, révélant les processus clés impliqués dans la progression de la maladie et de nouvelles approches thérapeutiques prometteuses.

Septic Shock and Purpura Fulminans Due to Streptococcus pneumoniae Bacteremia in an Unvaccinated Immunocompetent Adult: Case Report and Review.

BACKGROUND Despite proven efficacy of vaccinations against Streptococcus pneumoniae in preventing infection, only 70% of eligible individuals receive the vaccine in the United States. Pneumococcal bacteremia represents a form of invasive pneumococcal disease and is associated with high mortality, especially in immunocompromised patients and the elderly. Purpura fulminans is a rare complication and manifestation of disseminated intravascular coagulation and sepsis. It is exceedingly rare in the setting of pneumococcal bacteremia, particularly in immunocompetent individuals. CASE REPORT We report a generally healthy 67-year-old male with schizophrenia who refused pneumococcal vaccination. He had an intact and functional spleen with a functional immune system. The patient presented with fever and diarrhea. He subsequently progressed to develop purpura fulminans and septic shock due to S. pneumoniae bacteremia. Despite an extensive search for the primary source of infection, none could not be identified. Due to timely initiation of appropriate antibiotic therapy and aggressive supportive care in an intensive care unit, he recovered despite multi-organ failure that developed throughout his hospitalization. CONCLUSIONS We present a rare manifestation of a potentially preventable disease and emphasize the importance of pneumococcal vaccination in order to decrease the risk of developing invasive pneumococcal disease. Furthermore, we discuss etiology, diagnosis, differential diagnosis, and evidence-based management of purpura fulminans and invasive pneumococcal disease with a literature review. Purpura fulminans due to S. pneumoniae is exceedingly rare in immunocompetent patients and an unusual clinical manifestation of pneumococcal bacteremia.

Successful treatment of meningococcal bacteremia using oral doxycycline: A case report.

We report the case of an 18-year-old immunocompetent man who presented to the hospital with fever, headaches, and arthromyalgia, which progressed to include an erythematous rash. He had a history of a tick bite 72 h earlier. The diagnosis of rickettsial infection was suspected and a course of doxycycline was initiated for a total of 5 days. His evolution was rapidly favorable under treatment, with resolution of the symptoms within 24 h. Blood cultures came back positive for Neisseria meningitidis serotype B, indicating an authentic purpura fulminans. Purpura fulminans is a medical emergency, a syndrome of intravascular thrombosis characterized by a very rapid evolution that requires early recognition and specific treatment. It is commonly described in the young and healthy patient and has high mortality and morbidity. Common bacteria mainly associated with purpura fulminans are Meningococcus spp., Pneumococcus spp., and Staphylococcus spp.

Successful Corticosteroid Treatment for Purpura Fulminans Associated with Quinolone.

Purpura fulminans (PF) is a life-threatening syndrome comprising progressive hemorrhagic necrosis due to disseminated intravascular coagulation and dermal vascular thrombosis that leads to purpura and tissue necrosis. Various therapies have been used to arrest the progression of this disease, however, there is no established treatment because of the variety of underlying causes. We herein present an adult case of PF associated with leukocytoclastic vasculitis triggered by antibiotic (levofloxacin) intake. As a result of our rapid and accurate identification of the underlying cause, corticosteroid therapy successfully repressed the inflammatory process. As far as we know, this is the first report of levofloxacin-associated PF.

Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency.

Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs. Fifteen enrolled patients with SCPCD received protein C concentrate; 11 received treatment for acute TEs (PF, 18 events; PF and other coumarin-related vascular thromboembolic events [coumarin-induced skin necrosis; CISN], 1 event; venous thrombosis, 5 events). Pre-defined efficacy criteria for treatment of acute TEs were compared with a historical control arm (i. e. patients receiving conventional therapy without protein C replacement). PF/CISN was demonstrated by pre-defined primary and secondary efficacy ratings. Primary ratings of protein C concentrate-treated episodes were significantly higher (p=0.0032) than in the historical control. For 19 PF/CISN episodes in 11 patients, 94.7 % of treatments were rated effective and 5.3 % effective with complications (not related to protein C concentrate). In a secondary efficacy rating, all treatments were rated effective (68.4 % excellent; 21.1 % good; 10.5 % fair). For 5/24 vascular thrombosis episodes, 80 % of treatments were rated excellent and 20 % were rated good. No treatment-related adverse events or serious adverse events occurred. In conclusion, protein C concentrate provides an efficacious, safe treatment for PF, CISN, and other TEs in SCPCD patients.

Skin Necrosis and Purpura Fulminans in Children With and Without Thrombophilia--A Tertiary Center's Experience.

Purpura fulminans (PF) is a very rare clinicopathologic skin disorder comprising dermal microvascular thrombosis associated with perivascular hemorrhage of multiple origins. It may occur as the presenting symptom of severe congenital deficiency of protein C (PC) or protein S (PS) during the newborn period, or later in life following oral anticoagulant therapy with vitamin K antagonists, or of sepsis that may be associated with disseminated intravascular coagulation. Treatment consists of anticoagulants and PC concentrates during acute episodes. We report our experience in the diagnosis and management of pediatric PF. The medical records of the 6 children aged 2-16 years (median: 5 years) who presented with PF to our tertiary care center between 1996 and 2013 were studied. The thrombophilia workup revealed either the presence of congenital homozygous PC deficiency, prothrombotic polymorphisms (factor V Leiden and FIIG20210A heterozygosity), acquired PC/PS deficiency, or no discernible thrombophilia. The skin necrosis resolved following conservative fresh-frozen plasma/anticoagulant therapy in 2 cases, whereas 3 children required interventional plastic surgery. The sixth case, a 10-year-old child with severe PC deficiency, heterozygous factor V Leiden, and FIIG20210A, received recombinant activated PC. PF in childhood is rare and has multiple etiologies. Understanding of the variable pathogenesis and risk factors will facilitate diagnosis and appropriate clinical management.

[Purpura fulminans of the adult--a hematological emergency]. / Purpura fulminans des Erwachsenen--ein hämatologischer Notfall.

HISTORY AND CLINICAL FINDINGS: A 51-year-old female patient with history of longterm drug abuse, was admitted to our hospital with large, stocking-shaped areas of painful, non-displaceable confluent bruising reaching up to the groin. INVESTIGATIONS: The emergency laboratory tests showed leucopenia, thrombocytopenia and anemia as well as a distinct protein C deficiency. DIAGNOSIS, TREATMENT AND COURSE: Purpura fulminans was diagnosed and treated with an initial dose of protein C. The patient survived and the skin necrosis can be treated. CONCLUSION: Purpura fulminans is an internistic and dermatological emergency situation which can lead to shock through consumptive coagulopathy. The serious course of disease can be prevented by rapid treatment with protein C.

[Impact of corticosteroids in the immediate management of invasive meningococcal disease associated with hyperinvasive strains of the ST-11 clonal complex in children]. / Impact des corticoïdes dans la prise en charge immédiate des infections invasives à méningocoque liées aux souches hyper-invasives du complexe clonal ST-11 chez l'enfant.

OBJECTIVES: We used data from the Groupe de pathologie infectieuse pédiatrique and Association clinique et thérapeutique infantile du Val-de-Marne (GPIP/ACTIV) National Survey of Bacterial Meningitis in children and the National Reference Center for Meningococci (CNRM) microbiological data to assess the potential impact of corticosteroids on the immediate management of invasive meningococcal disease (IMD) associated with different genotypes, including highly pro-inflammatory strains of the ST-11 clonal complex (genotype ST-11). METHODS: From 2001 to 2009, 259 pediatric wards and 168 microbiology laboratories distributed throughout France prospectively included all under-18-year-old patients with IMD (meningitis or purpura fulminans). The strains were sent to the CNRM for genotyping. We linked the ACTIV clinical data of IMD cases, where information on corticosteroid therapy was available, to strains isolated by the CRNM. RESULTS: A total of 1981 IMD cases were identified during the 8-year study, 805 cases (712 [88.5%] bacterial meningitis and 93 [11.5%] purpura fulminans) had steroid treatment data (33.8% received corticosteroids). The genotype of the strains was available for 410 patients (24.4% related to genotype ST-11; 100 patients). For all cases and regardless of the corticosteroids, mortality was significantly associated with the genotype ST-11 (OR=2.39, 95% CI [1.29; 4.42], P=0.004). For all cases and regardless of the genotypes of the isolates, mortality was also significantly higher for children with than without corticosteroid therapy (12.7% versus 4.5%, P<0.001). However, this treatment had been prescribed more frequently in severe cases, including shock, PF, coma and/or mechanical ventilation. For children who did not receive corticosteroids, the mortality rate was significantly higher with genotype ST-11 compared to other genotypes (OR=4.68 [1.91, 11.46], P=0.001). This difference disappeared in children who received corticosteroids. CONCLUSION: This study indicates that in the absence of corticosteroids, higher mortality in invasive meningococcal disease is associated with the ST-11 clonal complex strains. This suggests a possible positive effect of corticosteroid therapy depending on the genotype of the strain involved.

Purpura fulminans associated with Streptococcus pneumoniae septicemia in an asplenic pediatric patient.

Purpura fulminans is a rapidly progressive syndrome of small-vessel thrombosis and hemorrhagic necrosis of the skin accompanied by disseminated intravascular coagulation. We describe a case of Streptococcus pneumoniae septicemia in an asplenic 5-year-old boy on oral tacrolimus, with a past medical history of multivisceral organ transplantation and subsequent development of purpura fulminans on his chest and distal extremities. The acute infectious form of purpura fulminans is usually caused by gram-negative bacteria. Cases secondary to gram-positive encapsulated bacteria usually occur when individuals are immuno-suppressed or have anatomic or functional asplenia. Our patient had both, which likely increased his susceptibility, and he responded well to antimicrobial therapy in addition to prophylactic coverage in the setting of his immunosuppression. We review the literature for similar cases due to S. pneumoniae in the pediatric population and discuss the etiology and treatment of purpura fulminans.

Paediatric presentation and outcome of congenital protein C deficiency in Japan.

Severe heritable protein C (PC) deficiency is quite rare, although heterozygous PROC mutation is the second leading cause of genetic predisposition to thrombosis in Japanese adults. The aim of the study was to search the optimal management, the paediatric onset and outcomes of PC deficiency were characterized in Japan. The genetic study, postmarketing survey of activated PC(aPC) concentrate (Anact(®)C) and intensive review in Japan for 20 years enabled the analysis of the disease onset, genotype, treatment and prognosis. Symptomatic PC deficiency was determined in 27 Japanese children. All but two patients presented within 16 days after birth (three prenatal and six neonatal onsets). Postnatal-onset cases had normal growth at full-term delivery. Of the 27 patients, 19 suffered intracranial thrombosis or haemorrhage (ICTH) (three foetal hydrocephalies), 16 developed purpura fulminans (PF) and 10 had both at the first presentation. ICTH preceded PF in both affected cases. Low PC activities of 18 mothers and/or 12 fathers indicated 20 inherited PC deficiencies (2 homozygotes, 11 compound heterozygotes and 7 heterozygotes) and seven unidentified causes of PC deficiency. Nine of 11 patients studied had PROC mutations. Four unrelated patients (50%) carried PC nagoya (1362delG). No PC-deficient parents had experienced thromboembolism. Of the 18 patients with aPC therapy, two died and eight evaluable survivors had neurological sequelae. This first comprehensive study of paediatric PC deficiency suggested that perinatal ICTH was the major presentation, occurring earlier than neonatal PF. PC nagoya was prevalent in paediatric, but not adult, patients in Japan. Early maternal screening and optimal PC therapy are required for newborns at risk of PC deficiency.

Purpura fulminans in a patient with mixed connective tissue disease.

A 43-year-old lady was admitted to the intensive care unit with sepsis. She had a history of mixed connective tissue disease, Raynaud's syndrome and hypothyroidism. 2 days later, she developed a purpuric rash on her face and extremities with a livedoid background. Few days later, her distal fingers and toes became gangrenous which then had to be amputated. Laboratory investigations showed that she was coagulopathic and had multiple organ dysfunctions. Antiphospholipid antibodies were negative; however, protein C and antithrombin III levels were low. A skin biopsy showed fibrinoid necrosis in the vessel wall with microthrombi and red-cell extravasation. A diagnosis of purpura fulminans was made.

Neonatal purpura fulminans due to methicillin resistant Staphylococcus aureus.

Neonatal purpura fulminans is rare and may be inherited or acquired. It may ultimately lead to multiorgan failure and death. Purpura fulminans in a premature neonate resulting from Staphylococcus aureus septicemia is illustrated. Unfortunately, the baby succumbed to septicemia.

Long-term subcutaneous protein C replacement in neonatal severe protein C deficiency.

We describe here the case of a boy who presented 2 days after birth with purpura fulminans on his feet and scalp. Laboratory investigations revealed signs of disseminated intravascular coagulation. An underlying coagulation disorder was suspected, and therapy with recombinant tissue plasminogen activator, fresh-frozen plasma, and unfractionated heparin was started. On the basis of plasma protein C activity and antigen levels of 0.02 and 0.03 IU/mL, respectively, after administration of fresh-frozen plasma, a diagnosis of severe protein C deficiency was established, and therapy with intravenous protein C concentrate (Ceprotin [Baxter, Deerfield, IL]) was started. Because of difficulties with venous access, we switched to subcutaneous administration after 6 weeks. The precise dosing schedule for subcutaneously administered protein C concentrate is unknown. In the literature, a trough level of protein C activity at >0.25 IU/mL is recommended to prevent recurrent thrombosis. During 1 year of follow-up our patient frequently had protein C activity levels at <0.25 IU/mL. Clinically, however, there was no recurrent thrombosis, and we kept the dosage unchanged. This report highlights 2 important points: (1) subcutaneously administered protein C concentrate is effective in treating severe protein C deficiency; and (2) in accordance with previous studies, after the acute phase trough levels of protein C activity at >0.25 IU/mL may not be necessary to prevent recurrent thrombosis. However, further research on the dosing, efficacy, and safety of protein C concentrate for prophylaxis and treatment of severe protein C deficiency is needed.