Pathological Mechanisms and Novel Testing Methods in Thrombotic Thrombocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon, but potentially disabling or even deadly, thrombotic microangiopathy with a well-studied mechanism of ADAMTS13 deficiency or dysfunction. While established treatments are largely effective, the standard ADAMTS13 testing required to definitively diagnose TTP may cause delays in diagnosis and treatment, highlighting the need for rapid and effective diagnostic methods. Additionally, the heterogeneous presentation and varied inciting events of TTP suggest more variation in its mechanism than previously thought, implying three potential pathways rather than the accepted two. The recent discovery of ADAMTS13 conformation as a potential contributor to TTP in addition to the proposal of using the absolute immature platelet count (A-IPC) as a biomarker, present novel areas for monitoring and treatment. A-IPC in particular may serve as a more rapid and accurate diagnostic test to distinguish TTP from non-TTP TMAs and to monitor treatment response and relapse. These considerations highlight the need to further study TTP in order to improve best practices and patient care.

Retinoic Acid-Induced Regulation of Inflammatory Pathways Is a Potential Sepsis Treatment.

Sepsis is among the most dangerous known diseases, resulting from the dysregulation of the innate immune system in a process that is characterized largely by proinflammatory cytokines. It manifests as an excessive immune response to a pathogen and often leads to life-threatening complications such as shock and multiple-organ failure. Within the past several decades, much progress has been made to better understand the pathophysiology of sepsis and improve treatment. However, the average case-fatality rate for sepsis remains high. Current anti-inflammatory therapeutics for sepsis are not effective for use as first-line treatments. Focusing on all-trans-retinoic acid (RA), or activated vitamin A, as a novel anti-inflammatory agent, we have shown both in vitro and in vivo that RA decreases the production of proinflammatory cytokines. In vitro studies using mouse RAW 264.7 macrophages show that RA decreases tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) and increases mitogen-activated protein kinase phosphatase 1 (MKP-1). RA treatment was also associated with the reduced phosphorylation of key inflammatory signaling proteins. Using a lipopolysaccharide and cecal slurry sepsis model, we found that RA significantly reduced mortality rates in mice, downregulated proinflammatory cytokine production, decreased neutrophil infiltration into lung tissue, and reduced the destructive lung histopathology typically seen in sepsis. We propose that RA may increase the function of native regulatory pathways and serve as a novel treatment for sepsis.

Characterization of Pathogenic Sepsis Etiologies and Patient Profiles: A Novel Approach to Triage and Treatment.

Pathogenic sepsis is not a monolithic condition. Three major types of sepsis exist within this category: bacterial, viral, and fungal, each with its own mechanism of action. While similar in symptoms, the etiologies and immune mechanisms of these types differ enough that a discrete patient base can be recognized for each one. Non-specific treatment, such as broad-spectrum antibiotics, without determination of sepsis origins may worsen sepsis symptoms and leads to increased morbidity and mortality in patients. However, recognition of current and historical patterns in likely patients for each sepsis type may aid in differentiation between pathogens prior to definitive blood testing. Clinicians may ultimately be able to diagnose and treat bacterial, viral, and fungal sepsis using analysis of previous patient patterns and circumstances in addition to standard care. This method is likely to decrease incidence of multidrug-resistant organisms, organ failure due to ineffective treatment, and turnaround time to the correct treatment for each sepsis patient. Ultimately, we aim to provide classification information on these patient populations and to suggest epidemiology-based screening methods that can be integrated into critical care medicine, specifically triage and treatment of sepsis.

A Novel Combination of Biomarkers to Herald the Onset of Sepsis Prior to the Manifestation of Symptoms.

Sepsis, which kills over 200,000 patients and costs over $20 billion in the United States alone, presents a constant but preventable challenge in the healthcare system. Among the more challenging problems that it presents is misdiagnosis due to conflation with other inflammatory processes, as its mechanisms are identical to those of other inflammatory states. Unfortunately, current biomarker tests can only assess the severity and mortality risk of each case, whereas no single test exists that can predict sepsis prior to the onset of symptoms for the purpose of pre-emptive care and monitoring. We propose that a single test utilizing three, rather than two, biomarkers that appear most quickly in the blood and are the most specific for sepsis rather than trauma, may improve diagnostic accuracy and lead to lessened patient morbidity and mortality. Such a test would vastly improve patient outcomes and quality of life, prevent complications for sepsis survivors, and prevent hospital readmissions, saving the American healthcare system money. This review summarizes the current use of sepsis biomarkers to prognosticate morbidity and mortality, and rejects the current single-biomarker and even combination biomarker tests as non-specific and inaccurate for current patient needs/pro-inflammatory cytokines, general markers of inflammation, and proteins specific to myeloid cells (and therefore to infection) are discussed. Ultimately, the review suggests a three-biomarker test of procalcitonin (PCT), interleukin-6 (IL-6), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) to diagnose sepsis before the onset of symptoms.