Persistence of endothelial thrombomodulin in a patient with infectious purpura fulminans treated with protein C concentrate.
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ABSTRACT:
SUBMITTER: Bendapudi PK
PROVIDER: S-EPMC6234356 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
Publications
Persistence of endothelial thrombomodulin in a patient with infectious purpura fulminans treated with protein C concentrate.
Bendapudi Pavan K PK Robbins Alissa A LeBoeuf Nicole N Pozdnyakova Olga O Bhatt Ami A Duke Fujiko F Sells Ryan R McQuiston John J Humrighouse Ben B Rouaisnel Betty B Colling Meaghan M Stephenson Kathryn E KE Saavedra Arturo A Losman Julie-Aurore JA
Blood advances 20181101 21
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Project description:Purpura fulminans is a deadly complication of Neisseria meningitidis infections due to extensive thrombosis of microvessels. Although a Disseminated Intra-vascular Coagulation syndrome (DIC) is frequently observed during Gram negative sepsis, it is rarely associated with extensive thrombosis like those observed during meningococcemia, suggesting that the meningococcus induces a specific dysregulation of coagulation. Another specific feature of N. meningitidis pathogenesis is its ability to colonize microvessels endothelial cells via type IV pili. Importantly, endothelial cells are key in controlling the coagulation cascade through the activation of the potent anticoagulant Protein C (PC) thanks to two endothelial cell receptors among which the Endothelial Protein C Receptor (EPCR). Considering that congenital or acquired deficiencies of PC are associated with purpura fulminans, we hypothesized that a defect in the activation of PC following meningococcal adhesion to microvessels is responsible for the thrombotic events observed during meningococcemia. Here we showed that the adhesion of N. meningitidis on endothelial cells results in a rapid and intense decrease of EPCR expression by inducing its cleavage in a process know as shedding. Using siRNA experiments and CRISPR/Cas9 genome edition we identified ADAM10 (A Disintegrin And Metalloproteinase-10) as the protease responsible for this shedding. Surprisingly, ADAM17, the only EPCR sheddase described so far, was not involved in this process. Finally, we showed that this ADAM10-mediated shedding of EPCR induced by the meningococcal interaction with endothelial cells was responsible for an impaired activation of Protein C. This work unveils for the first time a direct link between meningococcal adhesion to endothelial cells and a severe dysregulation of coagulation, and potentially identifies new therapeutic targets for meningococcal purpura fulminans.
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Project description:BackgroundCutaneous manifestations of purpura fulminans (PF) present many challenges for clinicians and surgeons. In a state of septic shock complicated by limb ischemia, surgical interventions are necessary to control the pathological cascade and improve patient outcomes. The objective of this article was to report etiologies and surgical outcomes associated with cutaneous manifestations in adults.MethodsThis systematic review and meta-analysis compared 190 adult patients with etiologies, signs and symptoms, and surgical outcomes associated with cutaneous manifestations of PF. The PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases were systematically and independently searched. Patient and clinical characteristics, surgical interventions, outcomes, and complications were recorded.ResultsSeventy-nine studies were eligible for the systematic review, and 77 were eligible for meta-analysis using Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and Cochrane guidelines. A total of 71/190 (38%) cases reported surgical debridement. Fasciotomies were reported in 12/190 (6%) cases and 20 procedures. Amputations were reported in 154/190 (81%) cases. Reconstruction was reported in 45 cases. Skin grafts were applied in 31 cases. Flaps were used for reconstruction in 28 cases. Median (IQR) surgical procedures per patient were 4 (4, 5) procedures. Infectious organisms causing PF were 32% Neisseria meningitidis (n = 55) and 32% Streptococcus pneumonia (n = 55). Coagulase-negative Staphylococcus (95% confidence interval (CI)(8.2-177.9), p = 0.032), Haemophilus influenza (95%CI (7.2-133), p = 0.029), Streptococcus pneumonia (95% CI (13.3-75.9), p = 0.006), and West Nile Virus (95%CI (8.2-177.9), p = 0.032) were associated with significantly more extensive amputations compared to other organisms.ConclusionThis systematic review and patient-level meta-analysis found the most common presentation of PF was septic shock from an infectious organism. Neisseria meningitidis and Streptococcus pneumonia were equally the most common organisms associated with PF. The majority of cases were not treated in a burn center. The most common surgeries were amputations, with below-the-knee-amputations being the most common procedure. Skin grafting was the most commonly performed reconstructive procedure. The most common complications were secondary infections. Organisms with significantly more extensive amputations were coagulase-negative Staphylococcus, Haemophilus influenza, Streptococcus pneumonia, and West Nile Virus. Interpretation of findings should be cautioned due to limited sample data.
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Project description:The complete genome sequences of 11 Japanese Streptococcus pneumoniae isolates were determined by hybrid assembly of long and short reads, including two strains isolated from patients with acute infectious purpura fulminans, six strains from patients with sepsis, and three strains from patients with pneumonia.
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Project description:Purpura fulminans (PF) is a haematologic emergency that can occur in the setting of severe septic shock. Its pathophysiology is not well-understood; however, some evidence suggests it may be mediated by excessive protein C consumption. In this case report, we describe a patient with PF secondary to methicillin-resistant Staphylococcus aureus endocarditis. She presented with severe septic shock and, despite haemodynamic improvement, developed a significant purpuric rash. Diagnostic work-up was notable for severely decreased serum levels of protein C. This patient was successfully treated with protein C concentrate and surgical valve replacement. While PF is rarely associated with S. aureus infection, this presentation may be more frequently encountered among clinicians in the current opioid epidemic. Quick recognition is crucial and a multidisciplinary approach, including intravenous infusion of protein C, may be considered.
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Project description:AbstractExtreme disease phenotypes can provide key insights into the pathophysiology of common conditions, but studying such cases is challenging due to their rarity and the limited statistical power of existing methods. Herein, we used a novel approach to pathway-based mutational burden testing, the rare variant trend test (RVTT), to investigate genetic risk factors for an extreme form of sepsis-induced coagulopathy, infectious purpura fulminans (PF). In addition to prospective patient sample collection, we electronically screened over 10.4 million medical records from 4 large hospital systems and identified historical cases of PF for which archived specimens were available to perform germline whole-exome sequencing. We found a significantly increased burden of low-frequency, putatively function-altering variants in the complement system in patients with PF compared with unselected patients with sepsis (P = .01). A multivariable logistic regression analysis found that the number of complement system variants per patient was independently associated with PF after controlling for age, sex, and disease acuity (P = .01). Functional characterization of PF-associated variants in the immunomodulatory complement receptors CR3 and CR4 revealed that they result in partial or complete loss of anti-inflammatory CR3 function and/or gain of proinflammatory CR4 function. Taken together, these findings suggest that inherited defects in CR3 and CR4 predispose to the maladaptive hyperinflammation that characterizes severe sepsis with coagulopathy.
| S-EPMC10950473 | biostudies-literature
Project description:We report a series of 5 case-patients who had Israeli spotted fever, of whom 2 had purpura fulminans and died. Four case-patients were given a diagnosis on the basis of PCR of skin biopsy specimens 3-4 days after treatment with doxycycline; 1 case-patient was given a diagnosis on the basis of seroconversion. Rickettsia spp. from the 2 case-patients who died were sequenced and identified as Rickettsia conorii subsp. israelensis. Purpura fulminans has been described in association with R. rickettsii and R. indica, but rarely with R. conorii subsp. israelensis.
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Project description:IntroductionIdiopathic purpura fulminans (IPF) is a rare and severe coagulation disorder, associated with transient anti-protein S (anti-PS) antibodies in the context of post-viral infection such as varicella. Anti-protein S antibodies are frequently found in the context of varicella, in contrast with the rarity of IPF. Other factors such as anti-phospholipid antibodies (APL) and inherited thrombophilia may be associated with severe vascular complication.MethodThis is an ancillary study of a French multicenter retrospective series and systematic review of literature. We analyzed patients who were tested for inherited thrombophilia, namely antithrombin, protein C, protein S deficiency; prothrombin gene G20210A polymorphism (FII:G20210A),Factor V R506Q polymorphism (FV:R506Q); and/or for APL (lupus anticoagulant (LA), anti-cardiolipin antibodies (ACL), or anti-beta 2-GPI antibodies (Aβ2GP1).ResultsAmong the 25 patients tested for inherited thrombophilia, 7 (28%) had positive results. Three had FV R506Q, two FII:G20210A, one compound heterozygote FV:R506Q associated to FII:G20210A, and one protein C deficiency. APL testing was performed in 32 patients. It was positive in 19 patients (59%): 17 ACL (53%), 5 LA (16%), 4 Aβ2GP1 (13%). The risk of severe complications was not associated with presence of inherited thrombophilia or APL presence, with RR: 0.8 [95% CI: 0.37-1.71], p = 1 and RR: 0.7 [95% CI: 0.33-1.51], p = 0.39, respectively. We found a high prevalence of inherited thrombophilia or APL in a population of patients with IPF. However, we do not find an association with the occurrence of severe vascular complications or venous thromboembolism.
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Project description:BackgroundNeisseria meningitidis is the leading responsible bacterium of Purpura Fulminans (PF) accounting for two thirds of PF. Skin biopsy is a simple and minimally invasive exam allowing to perform skin culture and polymerase chain reaction (PCR) to detect Neisseria meningitidis. We aimed to assess the sensitivity of skin biopsy in adult patients with meningococcal PF.MethodsA 17-year multicenter retrospective cohort study including adult patients admitted to the ICU for a meningococcal PF in whom a skin biopsy with conventional and/or meningococcal PCR was performed.ResultsAmong 306 patients admitted for PF, 195 had a meningococcal PF (64%) with a skin biopsy being performed in 68 (35%) of them. Skin biopsy was performed in median 1 day after the initiation of antibiotic therapy. Standard culture of skin biopsy was performed in 61/68 (90%) patients and grew Neisseria meningitidis in 28 (46%) of them. Neisseria meningitidis PCR on skin biopsy was performed in 51/68 (75%) patients and was positive in 50 (98%) of them. Among these 50 positive meningococcal PCR, five were performed 3 days or more after initiation of antibiotic therapy. Finally, skin biopsy was considered as contributive in 60/68 (88%) patients. Identification of the meningococcal serogroup was obtained with skin biopsy in 48/68 (71%) patients.ConclusionsSkin biopsy with conventional culture and meningococcal PCR has a global sensitivity of 88% and should be systematically considered in case of suspected meningococcal PF even after the initiation of antimicrobial treatment.
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Project description:IntroductionPurpura fulminans is a rare but fatal manifestation of Capnocytophaga canimorsus bacteremia that can present in immunocompromised hosts. This can have a profound impact on patients, including recipients of allogeneic hematopoietic stem cell transplant. Despite aggressive therapy, mortality can be as high as 60% and most patients require amputation of multiple extremities.Case presentationWe present a 31-year-old woman s/p myeloablative allogeneic transplant, presenting with purpura fulminans and septic shock. She had been on Immunosuppressive therapy with rituximab and tacrolimus. Despite aggressive antibiotic coverage and supportive therapy, although her shock was resuscitated, she had to undergo bilateral below-knee amputations.DiscussionWe attempt to highlight the clinical presentation, pathophysiology and potential therapeutic options for immunocompromised patients presenting with septic shock from C. canimorsus. The importance of pre-transplant counselling on handling and adoption of new pets to prevent zoonotic infections is also discussed. Early recognition and initiation of antibiotics play a crucial role to reduce mortality in patients receiving HSCT.
| S-EPMC11521502 | biostudies-literature