Thrombolome and Its Emerging Role in Chronic Kidney Diseases.

Patients with chronic kidney disease (CKD) are at an increased risk of thromboembolic complications, including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. These complications lead to increased mortality. Evidence points to the key role of CKD-associated dysbiosis and its effect via the generation of gut microbial metabolites in inducing the prothrombotic phenotype. This phenomenon is known as thrombolome, a panel of intestinal bacteria-derived uremic toxins that enhance thrombosis via increased tissue factor expression, platelet hyperactivity, microparticles release, and endothelial dysfunction. This review discusses the role of uremic toxins derived from gut-microbiota metabolism of dietary tryptophan (indoxyl sulfate (IS), indole-3-acetic acid (IAA), kynurenine (KYN)), phenylalanine/tyrosine (p-cresol sulfate (PCS), p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln)) and choline/phosphatidylcholine (trimethylamine N-oxide (TMAO)) in spontaneously induced thrombosis. The increase in the generation of gut microbial uremic toxins, the activation of aryl hydrocarbon (AhRs) and platelet adrenergic (ARs) receptors, and the nuclear factor kappa B (NF-κB) signaling pathway can serve as potential targets during the prevention of thromboembolic events. They can also help create a new therapeutic approach in the CKD population.

The gut microbes, Enterococcus and Escherichia-Shigella, affect the responses of heart valve replacement patients to the anticoagulant warfarin.

Numerous algorithms based on patient genetic variants have been established with the aim of reducing the risk of GI bleeding and thromboembolism during warfarin administration. However, approximately 35 % of individual warfarin sensitivity still remains unexplained. Few of warfarin algorithms take into account gut microbiota profiles. The identification of certain microbiome will provide new targets and new strategies for reducing the risk of bleeding and thromboembolism during warfarin administration. In this study, we collected plasma and stool samples from 200 inpatients undergoing heart valve replacement (HVR), which were classified as low responder (LR), high responder (HR) and normal responder (NR). Significant differences were observed in the diversity and relative abundance of the gut microbiota among the three groups. The genus Escherichia-Shigella was enriched significantly in the LRs (P = 3.189e-11), while the genus Enterococcus was enriched significantly in the HRs (P = 1.249e-11). The amount of VK2 synthesized by gut microbiota in LR group was much higher than that in HR group (P = 0.005). Whole genome shotgun sequencing indicated that the relative abundance of enzymes and modules associated with VK biosynthesis was significantly higher in LRs than in HRs or NRs. The 12 microbial markers were identified through tenfold cross-validation with a random forest model. The results provided a new microbial diagnostic model that can be used to inform modulation of warfarin dosage on the basis of patient intestinal flora composition.

Neurologic Complications of Infective Endocarditis: A Joint Model for a Septic Thromboembolism and Inflammatory Small Vessel Disease.

OBJECTIVES: Embolic events from vegetations are commonly accepted as the main mechanism involved in neurologic complications of infective endocarditis. The pathophysiology may imply other phenomena, including vasculitis. We aimed to define the cerebral lesion spectrum in an infective endocarditis rat model. DESIGN: Experimental model of Staphylococcus aureus or Enterococcus faecalis infective endocarditis. Neurologic lesions observed in the infective endocarditis model were compared with three other conditions, namely bacteremia, nonbacterial thrombotic endocarditis, and healthy controls. SETTING: Research laboratory of a university hospital. SUBJECTS: Male Wistar rats. INTERVENTIONS: Brain MRI, neuropathology, immunohistochemistry for astrocyte and microglia, and bacterial studies on brain tissue were used to characterize neurologic lesions. MEASUREMENTS AND MAIN RESULTS: In the infective endocarditis group, MRI revealed at least one cerebral lesion in 12 of 23 rats (52%), including brain infarctions (n = 9/23, 39%) and cerebral microbleeds (n = 8/23, 35%). In the infective endocarditis group, neuropathology revealed brain infarctions (n = 12/23, 52%), microhemorrhages (n = 10/23, 44%), and inflammatory processes (i.e., cell infiltrates including abscesses, vasculitis, meningoencephalitis, and/or ependymitis; n = 11/23, 48%). In the bacteremia group, MRI studies were normal and neuropathology revealed only hemorrhages (n = 2/11, 18%). Neuropathologic patterns observed in the nonbacterial thrombotic endocarditis group were similar to those observed in the infective endocarditis group. Immunochemistry revealed higher microglial activation in the infective endocarditis group (n = 11/23, 48%), when compared with the bacteremia (n = 1/11, 9%; p = 0.03) and nonbacterial thrombotic endocarditis groups (n = 0/7, 0%; p = 0.02). CONCLUSIONS: This original model of infective endocarditis recapitulates the neurologic lesion spectrum observed in humans and suggests synergistic mechanisms involved, including thromboembolism and cerebral vasculitis, promoted by a systemic bacteremia-mediated inflammation.

A novel in vitro model for haematogenous spreading of S. aureus device biofilms demonstrating clumping dispersal as an advantageous dissemination mechanism.

Staphylococcus aureus is able to disseminate from vascular device biofilms to the blood and organs, resulting in life-threatening infections such as endocarditis. The mechanisms behind spreading are largely unknown, especially how the bacterium escapes immune effectors and antibiotics in the process. Using an in vitro catheter infection model, we studied S. aureus biofilm growth, late-stage dispersal, and reattachment to downstream endothelial cell layers. The ability of the released biofilm material to resist host response and disseminate in vivo was furthermore studied in whole blood and phagocyte survival assays and in a short-term murine infection model. We found that S. aureus biofilms formed in flow of human plasma release biofilm thromboemboli with embedded bacteria and bacteria-secreted polysaccharides. The emboli disseminate as antibiotic and immune resistant vehicles that hold the ability to adhere to and initiate colonisation of endothelial cell layers under flow. In vivo experiments showed that the released biofilm material reached the heart similarly as ordinary broth-grown bacteria but also that clumps to some extend were trapped in the lungs. The clumping dispersal of S. aureus from in vivo-like vascular biofilms and their specific properties demonstrated here help explain the pathophysiology associated with S. aureus bloodstream infections.

Renal embolism as a primary manifestation of Streptococcus dysgalactiae subspecies equisimilis endocarditis in a patient with chronic aortic dissection.

We report a case of renal embolism as an initial manifestation of Streptococcus dysgalactiae subspecies equisimilis (SDSE) endocarditis in a patient with chronic aortic dissection. A 37-year-old man who underwent total aortic arch replacement owing to aortic dissection, presented with a 3-h history of fever, chills, and acute right-sided flank pain. The endocarditis affected the native aortic valve and was complicated by a renal embolism. Blood culture results were positive for SDSE. Intravenous penicillin resulted in satisfactory clinical and echocardiographic recovery.

Staphylococcal endocarditis as the first manifestation of heritable protein S deficiency in childhood.

A 12-year-old Japanese girl developed infective endocarditis and central nervous system disease. The previously healthy girl showed altered consciousness and abnormal behaviors along with the classical signs of septic emboli. Staphylococcus aureus was isolated from peripheral blood, but not, the pleocytotic cerebrospinal fluid. Diagnostic imaging studies revealed a vegetative structure in the morphologically normal heart, and multiple thromboembolisms in the brain and spleen. Low plasma activity of protein S (12%) and thrombophilic family history allowed the genetic study, demonstrating that she carried a heterozygous mutation of PROS1 (exon 13; 1689C > T, p.R474C). Surgical intervention of the thrombotic fibrous organization and subsequent anticoagulant therapy successfully managed the disease. There are no reports of infective endocarditis in childhood occurring as the first presentation of heritable thrombophilia. Protein S deficiency might be a risk factor for the development or exacerbation of infective endocarditis in children having no pre-existing heart disease.

Septic emboli resulting in an acutely ischaemic lower limb: a case report.

Sources of arterial embolism range from the common, such as cardiac pathology, to less common causes. We present a case of an acutely ischaemic lower limb due to septic emboli from Staphylococcus aureus pneumonia.

Native valve endocarditis and femoral embolism due to Granulicatella adiacens: a rare case report

The fastidious Gram-positive cocci Granulicatella adiacens, previously known as nutritionally variant streptococci (NVS) are unusual but significant cause of endocarditis due to increased mortality and morbidity. Difficulties in reaching correct bacteriological identification, increased resistance to beta-lactam antibiotics and macrolides and complicated clinical course have contributed to problems in management of cases of infective endocarditis caused by this bacterium. We present the first Indian case of endocarditis with arterial embolus by G. adiacens in an elderly male with no preexisting cardiac abnormality.

First case of human "Candidatus Neoehrlichia mikurensis" infection in a febrile patient with chronic lymphocytic leukemia.

An immunocompromised patient presented with febrile episodes, an erysipelas-like rash, and thromboembolic complications. Amplification of 16S rRNA gene sequences from blood and sequence analysis revealed "Candidatus Neoehrlichia mikurensis." We report the first case of human disease caused by "Ca. Neoehrlichia mikurensis."

Native valve endocarditis and femoral embolism due to Granulicatella adiacens: a rare case report.

The fastidious Gram-positive cocci Granulicatella adiacens, previously known as nutritionally variant streptococci (NVS) are unusual but significant cause of endocarditis due to increased mortality and morbidity. Difficulties in reaching correct bacteriological identification, increased resistance to beta-lactam antibiotics and macrolides and complicated clinical course have contributed to problems in management of cases of infective endocarditis caused by this bacterium. We present the first Indian case of endocarditis with arterial embolus by G. adiacens in an elderly male with no preexisting cardiac abnormality.

High incidence of venous thromboembolic events in lung transplant recipients.

BACKGROUND: Previous studies have reported a 12% incidence of venous thromboembolic events (VTEs) in lung transplant recipients (LTRs). Characterization of risk factors for VTEs in LTRs is lacking. We identified the incidence and risk factors associated with post-transplant VTEs. METHODS: A retrospective review of 153 LTRs from 1994 to 2006 was performed. Patients were categorized by age, race, gender, weight, underlying diagnosis, procedure, ischemic time, length of stay (LOS), cardiopulmonary bypass (CPB), location and number of VTEs, mobility, immunosuppression, renal, hepatic, hematologic and coagulation profiles and nutritional status. RESULTS: A single VTE occurred in 29% of LTRs within the study period. Fifty-eight percent had multiple VTEs and 7% had a radiologically confirmed pulmonary embolism. Median time from transplant to first VTE was 69 days. Sixty percent of VTEs occurred within 1 year, 20% of which occurred within the first month, 19% between 2 and 5 years, and 13% at beyond 5 years post-transplant. Seventy-six percent of VTEs occurred during hospitalization, 19% during outpatient status. Forty-eight percent were of the upper extremity and 47% were of the lower extremity. Sixty-one percent of LTRs were taking cyclosporine and 39% tacrolimus. VTE and non-VTE groups were similar in age, weight, body mass index (BMI), ischemic time, procedure or underlying diagnosis precipitating the need for transplant. Univariate analysis revealed LOS and CPB as significant predictors of a single VTE (p = 0.036, hazard ratio [HR] 1.006 and p = 0.045, HR 1.91, respectively). Multivariate analysis revealed only CPB as a significant predictor (p = 0.047, HR 1.929). CONCLUSIONS: Analysis of a cohort of LTRs for a median period of 1.5 years revealed a VTE incidence much higher than previously reported, especially within the first month after transplantation.

[Infective endocarditis in an internal medicine ward]. / Estudio retrospectivo de la endocarditis infecciosa en diferentes grupos de riesgo.

BACKGROUND: Due to the increasing number of intravenous drug users, subjects with immune deficiencies or with prosthetic valves, infective endocarditis (IE) continues to be prevalent and to have a high mortality. AIM: To review all cases of infective endocarditis diagnosed in an Internal Medicine Service. MATERIAL AND METHODS: Retrospective review of medical records of all patients with infective endocarditis, hospitalized in an Internal Medicine ward, between 1989 and 2003. Dukes criteria were used to define definitive, possible and less probable cases of IE. RESULTS: Eighty seven patients with definite IE were identified (66 males, age range 19-84 years), with a mean incidence of 5.3 per 1000 hospitalizations. IE in intravenous drugs users was usually caused by Staphylococcus aureus and presented high risk of embolism (RR: 3,21). Subjects aged over 70 years had a relative risk of mortality of 5.5. Hospital acquired IE was associated with advanced age and IV catheters appeared as the only predisposing factor. Patients with prosthetic valves were also older, their main complication was abscess formation and their mortality was higher. CONCLUSIONS: A closer approach to differential conditions of patients, according to age, intravenous drug use or the presence of prosthetic valves, is necessary.

Estudio retrospectivo de la endocarditis infecciosa en diferentes grupos de riesgo / Infective endocarditis in an internal medicine ward

Background: Due to the increasing number of intravenous drug users, subjects with immune deficiencies or with prosthetic valves, infective endocarditis (IE) continues to be prevalent and to have a high mortality. Aim: To review all cases of infective endocarditis diagnosed in an Internal Medicine Service. Material and methods: Retrospective review of medical records of all patients with infective endocarditis, hospitalized in an Internal Medicine ward, between 1989 and 2003. Dukes criteria were used to define definitive, possible and less probable cases of IE. Results: Eighty seven patients with definite IE were identified (66 males, age range 19-84 years), with a mean incidence of 5.3 per 1000 hospitalizations. IE in intravenous drugs users was usually caused by Staphylococcus aureus and presented high risk of embolism (RR: 3,21). Subjects aged over 70 years had a relative risk of mortality of 5.5. Hospital acquired IE was associated with advanced age and IV catheters appeared as the only predisposing factor. Patients with prosthetic valves were also older, their main complication was abscess formation and their mortality was higher. Conclusions: A closer approach to differential conditions of patients, according to age, intravenous drug use or the presence of prosthetic valves, is necessary

Disseminated staphylococcal disease: report of one case.

Childhood septic arthritis is not only an uncommon presentation with polyarticular involvement, but is also rarely complicated with thromboembolism. We report a case of a 10-year-old boy who suffered multiple staphylococcal arthritis, deep vein thrombosis, pulmonary embolism, pericardial effusion and occlusion of the anterior parietal branch of the right middle cerebral artery. Oxacillin-sensitive Staphylococcus aureus was isolated from blood, synovial fluid and pericardial effusion. Intravenous six-week oxacillin combined with two-week gentamicin for eradicating the pathogen, arthrotomy for debridment and subcutaneous low-molecular-weight heparin for preventing further thromboembolism were administered during admission. In addition, surveys for immunodeficiency, connective tissue disease and hemostatic dysfunction produced negative findings. The patient was discharged with neither painful disability of involved joints nor neurological sequelae.

[Bacterially conditioned thromboembolism in dairy cows--a retrospective study of 31 necropsy cases with special consideration of the causative complex]. / Bakteriell bedingte Thrombembolie bei Milchkühen--eine retrospektive Auswertung von 31 Sektionsfällen unter besonderer Berücksichtigung des Ursachenkomplexes.

A study of 340 necropsied dairy cattle from northern Bavaria resulted in 31 animals (9%) showing evidence of pyemic thromboembolism. The most frequent pathomorphologic lesions consisted in endocarditis valvularis thromboticans of the tricuspid and/or mitral valve (21), embolic pneumonia (26), nephritis (13) and renal infarction (12). The most common isolate found in bacteriologic culture was Arcanobacterium pyogenes in 26 of 31 cases, followed by Staphylococcus aureus (2), Mannheimia haemolytica (2) and Streptococcus bovis (1) in rare cases. In 27 of 31 cows a possible cause of pyemic thromboembolism was found; in 23 cases claw diseases and decubital ulcera were probably responsible.