Abstract
This year, 2021, marks 70 years since the first systematic use of plasmapheresis in blood donors was described. In this revolutionary technique, which is still used worldwide as a standard procedure today, plasma is separated from whole blood while red cells and other blood components are reinfused into the donor’s circulatory system almost immediately after extraction. The procedure was developed by J. A. Grifols-Lucas and presented at the 4th International Congress of Blood Transfusion in Lisbon, Portugal, in July 1951 (Figure 1). This presentation was followed by a scientific article published in the British Medical Journal 1 . Plasmapheresis allowed donors to donate more frequently than was possible with whole blood without compromising their health. This made it possible to respond more effectively to the demand for plasma. Hence, the path was set for widespread plasma availability that allowed the study of its components for clinical, diagnostic and therapeutic applications. Destiny and fate have combined such that this year, 2021, is when Plasmatology, the first journal devoted to blood plasma science, comes into being.
Cover of the official program of the 4th International Congress of Blood Transfusion in Lisbon, Portugal in July 1951 (left panel), and page where the presentation on the first series of cases of plasmapheresis in humans by J. A. Grifols-Lucas is mentioned (right panel).
At a cursory glance, blood plasma might be seen as a passive character in the performance of blood circulation, little more than the theater stage with the mere roles of blood cell transporter and maintainer of blood pressure and volume. This is far from the case. Blood plasma is a rich component of the human body which has numerous vital functions. It is with good reason that plasma is always among the first samples to be examined for diagnostic and therapeutic purposes.
Transportation is the first function evidenced by the circulating nature of plasma. Primarily, nutrients are transported from the digestive system through plasma to different parts of the body and waste products from cellular metabolism are transported to their excretion sites. But there are many other compounds that confer upon plasma its singularity: nucleic acids, proteins, metabolites (carbohydrates and lipids) and electrolytes. Biological research to provide detailed knowledge of the plasma proteome, metabolome, lipidome and glycome is expected to lead to discovery of markers that will expand our diagnostic capabilities, establish prognoses, and monitor the progression of diseases and response to therapies.
Free nucleic acids found in plasma can be of genomic, mitochondrial or viral origin 2 . Mechanisms by which these nucleic acids can be released into circulation include apoptosis, necrosis, and even spontaneous release from cells. There is wide interest in the utility of circulating nucleic acids as biomarkers in cancer and neurological disorders.
Plasma proteins constitute the most complex human-derived proteome 3 . The number of proteins secreted by solid tissues that act in plasma is around 500 (with albumin being the most abundant making up about half of the protein content). This number is increased by 100-fold if we include all molecular forms such as precursors, functional forms, splice variants, post-translational modifications and degradation products. Furthermore, this number could be increased by 10,000,000 different sequences of immunoglobulin and 500,000 other proteins not acting in plasma, such as receptor ligands (e.g., peptides, protein hormones, cytokines and mediators of cellular responses), passenger proteins (temporarily in transit to their primary functional site), leakage products (the result of tissue damage or cell death), and proteins of pathological origin (released from tumors and diseased tissues, and proteins of infectious organisms). It is therefore no wonder that plasma proteome has become a major driving force in the field of biomarkers. In addition, most human proteins are glycosylated. The factors that influence the glycome are numerous, in ways that create a highly diverse and dynamic system 4 . Variation in the plasma glycome make-up correlates with disease development and response to drug therapies.
Plasma lipids are not far behind in interest due to their structural diversity, complexity, and the huge number ‒in the hundreds of thousands‒ of molecular species 5 . Lipid categories cover fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, and prenol lipids, with almost 600 distinct molecular species quantified. The lipids in plasma are solubilized and transported through their association with proteins. Free fatty acids typically associate with albumin, whereas more complex lipids are transported and distributed by means of plasma lipoproteins. Detailed knowledge of the composition and concentration of plasma lipidome could reveal novel molecular biomarkers and expand diagnostic capabilities.
Also concerning both lipids and proteins, extracellular vesicles constitute a major component of the plasma secretome 6 . Extracellular vesicles, mainly made up of microvesicles and exosomes, are shed from all cell types and play major roles in intercellular communication. Importantly, extracellular vesicles constitute a reliable and stable biomarker source, particularly for cancer and infectious diseases.
In addition to macromolecules, plasma contains small molecules such as endogenous metabolites, xenobiotics, dietary constituents and agents of environmental exposure 7 . The metabolome integrates an individual’s genetic background, age, diet, lifestyle and environmental factors. Therefore, changes in plasma levels of any of these metabolites can provide important information about alterations in both anabolic and catabolic processes, including those changes associated with aging and degenerative disease. Knowledge of plasma metabolomics can be applied to biological research, pharmaceutical discovery, biomarker identification, and disease diagnosis.
Since 2020, blood plasma is attracting particular attention because of the potential to treat COVID-19 with plasma from convalescent patients. However, lifesaving therapies from plasma have long been well-known for treating other infections as well as rare, chronic diseases such as alpha-1 antitrypsin deficiency, immune deficiency diseases, neurological disorders, von Willebrand disease and hemophilia. Moreover, the potential of plasma therapies for the treatment of Alzheimer’s disease has been recently demonstrated. Given this long history and recent developments, there is no doubt that plasma research has a very exciting and almost limitless future ahead.
With this first issue, Plasmatology begins its journey with two interelated aims: first, gathering the most relevant scientific knowledge on human plasma from basic and clinical research; and second, becoming the journal of reference for blood plasma science, to confer the recognition that this field deserves as a full fledged branch of medicine.