Sepsis is a serious clinical condition that represents a patient’s response to a severe infection and has a very high mortality rate. Normal immune and physiologic responses eradicate pathogens, and the pathophysiology of sepsis is due to the inappropriate regulation of these normal reactions. In an ideal scenario, the first pathogen contact with the inflammatory system should eliminate the microbe and quickly return the host to homeostasis. The septic response may accelerate due to continued activation of neutrophils and macrophages/monocytes. Upregulation of lymphocyte costimulatory molecules and rapid lymphocyte apoptosis, delayed apoptosis of neutrophils, and enhanced necrosis of cells/tissues also contribute to the pathogenesis of sepsis. The coagulation system is closely tied to the inflammatory response, with cross talk between the two systems driving the dysregulated response. Biomarkers may be used to help diagnose patients with sepsis, and they may also help to identify patients who would benefit from immunomodulatory therapies.

/pdf/the-pathogenesis-of-sepsis-1wqfmuezmj.pdf

The Pathogenesis of Sepsis

Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions.

Society of Interventional Radiology Consensus Guidelines for the Periprocedural Management of Thrombotic and Bleeding Risk in Patients Undergoing Percutaneous Image-Guided Interventions-Part II: Recommendations: Endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe.

Proteases are an expanding class of drugs that hold great promise. The U.S. FDA (Food and Drug Administration) has approved 12 protease therapies, and a number of next generation or completely new proteases are in clinical development. Although they are a well-recognized class of targets for inhibitors, proteases themselves have not typically been considered as a drug class despite their application in the clinic over the last several decades; initially as plasma fractions and later as purified products. Although the predominant use of proteases has been in treating cardiovascular disease, they are also emerging as useful agents in the treatment of sepsis, digestive disorders, inflammation, cystic fibrosis, retinal disorders, psoriasis and other diseases. In the present review, we outline the history of proteases as therapeutics, provide an overview of their current clinical application, and describe several approaches to improve and expand their clinical application. Undoubtedly, our ability to harness proteolysis for disease treatment will increase with our understanding of protease biology and the molecular mechanisms responsible. New technologies for rationally engineering proteases, as well as improved delivery options, will expand greatly the potential applications of these enzymes. The recognition that proteases are, in fact, an established class of safe and efficacious drugs will stimulate investigation of additional therapeutic applications for these enzymes. Proteases therefore have a bright future as a distinct therapeutic class with diverse clinical applications.

/pdf/proteases-as-therapeutics-1d6sokds4i.pdf

Proteases as therapeutics.

Heparin-Induced Thrombocytopenia: A Comprehensive Clinical Review

Cardiovascular disease is a leading cause of death and pathologic coagulation plays an integral role in the development, propagation, and intervention of cardiovascular disease. The 2 classic anticoagulants, heparin and vitamin K antagonists, though having served humanity for nearly a century, are both inconvenient and nonspecific. Through both direct and indirect roles, thrombin is essential to coagulation, and makes for a very attractive target in medical intervention of pathologic thrombosis. This article will review the nature of direct thrombin inhibitors, current indications, and ongoing trials.

Direct thrombin inhibitors.

Venous thoracic outlet syndrome secondary to first rib osteochondroma in a pediatric patient.

Blunt or penetrating trauma to the major arteries of the neck are challenging problems, however, newer diagnostic and therapeutic modalities have simplified care and largely eliminated the need for diagnostic neck exploration. High-quality computed tomographic angiography is quick and sensitive, identifying the vast majority of injuries prior to any operative intervention. Even in cases where active exsanguination or impending airway compromise mandates immediate exploration, intraoperative imaging and endovascular interventions have largely supplanted relatively morbid exposures for open repair. Traditional open repair of carotid injuries with primary closure or interposition grafting is effective over the long term and is always recommended if proximal and distal control can be achieved in a safe and straightforward manner. Endovascular repair of the proximal carotid, proximal subclavian, and distal internal carotid arteries is increasingly accepted. However, vertebral trauma is dealt with almost exclusively by endovascular means. Recent military experiences in Iraq and Afghanistan highlight the imaging-intensive management of cervical vascular trauma and demonstrate the effectiveness of computed tomography angiography, selective arteriography, and endovascular interventions.

A modern approach to cervical vascular trauma.

The diagnosis and treatment of venous thromboembolic events represents a significant source of medical spending, both domestically and worldwide. Advances in medical imaging and pharmacology continue to alter and improve established treatment paradigms. In this article, we discuss venous thromboembolism etiology, diagnosis, and rationale for current and future treatment strategies.

P. Joshua O’Brien

Papers

Direct thrombin inhibitors.

Venous thoracic outlet syndrome secondary to first rib osteochondroma in a pediatric patient.

A modern approach to cervical vascular trauma.

Venous thromboembolism: diagnosis and current anticoagulation strategies for deep vein thrombosis and pulmonary embolism.