The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer.

von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities.

Why is Misdiagnosis of von Willebrand Disease Still Prevalent and How Can We Overcome It? A Focus on Clinical Considerations and Recommendations.

Despite von Willebrand disease (VWD) being the most common inherited bleeding disorder, its accurate diagnosis is frequently shrouded by diagnostic pitfalls. VWD is frequently under-diagnosed, over-diagnosed and misdiagnosed, leading to significant avoidable patient morbidity and health care system burden. At the heart of this dilemma lies the heterogeneity and complexity of von Willebrand factor (VWF) and associated defects, and the necessity of coalescing clinical and laboratory features to obtain an accurate diagnosis. Common pitfalls include poor clinical and scientific understanding and familiarity with VWD, incomplete clinical history and lack of routine use of standardised bleeding assessment tools (BAT), difficulty in accessing a comprehensive repertoire of laboratory tests, significant pre-analytical, analytical and post-analytical issues, and lack of expertise in laboratory testing and interpretation. Errors, resulting in under-diagnosis, over-diagnosis, and misdiagnosis of VWD, are presented and discussed. Strategies to minimise errors include better education of clinicians and laboratory staff on VWD, routine use of validated BAT, utilising a comprehensive gamut of laboratory investigations according to a standardised algorithm, and repeating testing to minimise pre-analytical errors. Recommendations on appropriate patient selection for VWD testing, how VWD should be investigated in the laboratory, and how to ensure test results are accurately interpreted in the correct clinical context are detailed.

Identification and Analysis of Mouse Erythroid Progenitor Cells.

The most common cell type in the human body, the red blood cell or erythrocyte, has a life span of approximately 3 months. To compensate for this massive cellular requirement and short life span, the major blood producing tissues contain vast numbers of erythroid progenitor cells. Erythroid progenitors differentiate progressively from hematopoietic stem cells to committed erythroid progenitors to reticulocytes lacking a nucleus and finally to functionally mature erythrocytes in the circulation. Different erythroid progenitor activity, representative of distinct stages of erythropoiesis, can be observed using semisolid colony assays. Distinct stages of erythroid maturation can also be monitored by flow cytometry. Here, we discuss the range of different technical approaches that are used to identify and quantify erythroid progenitors, with particular focus on the mouse as a model system.

The iron islands: Erythroblastic islands and iron metabolism.

BACKGROUND: A healthy human can produce over 1 × 1015 blood cells throughout their life. This remarkable amount of biomass requires a concomitantly vast amount of iron to generate functional haemoglobin and functional erythrocytes. SCOPE OF THE REVIEW: Erythroblasts form multicellular clusters with macrophages in the foetal liver, bone marrow and spleen termed erythroblastic islands. How the central erythroblastic island macrophage co-ordinates the supply of iron to the developing erythroblasts will be a central focus of this review. MAJOR CONCLUSION: Despite being studied for over 60 years, the mechanisms by which the erythroblastic island niche serves to control erythroid cell iron metabolism are poorly resolved. GENERAL SIGNIFICANCE: Over 2 billion people suffer from some form of anaemia. Iron deficiency anaemia is the most prevalent form of anaemia. Therefore, understanding the processes by which iron is trafficked to, and metabolised in developing erythrocytes, is crucially important.

Splenomegaly: Pathophysiological bases and therapeutic options.

The spleen is the largest immune organ in the human body and is also essential for red blood cell homeostasis and iron recycling. An average human spleen is approximately 10 centimetres in length and weighs 150g. Pathological conditions can result in the spleen weighing in excess of 2000g and extending over 30 centrimetres in length. This remarkable property of the spleen to expand is termed splenomegaly. Splenomegaly can occur as a physiological response to stress or as a chronic process that is often detrimental to the wellbeing of the individual. Here, we will discuss the normal function and physiology of the spleen, the pathophysiological bases of splenomegaly and the commonly available therapeutic options. Additionally we will address experimental systems to determine the regulatory mechanisms underlying splenomegaly.

Making Blood: The Haematopoietic Niche throughout Ontogeny.

Approximately one-quarter of all cells in the adult human body are blood cells. The haematopoietic system is therefore massive in scale and requires exquisite regulation to be maintained under homeostatic conditions. It must also be able to respond when needed, such as during infection or following blood loss, to produce more blood cells. Supporting cells serve to maintain haematopoietic stem and progenitor cells during homeostatic and pathological conditions. This coalition of supportive cell types, organised in specific tissues, is termed the haematopoietic niche. Haematopoietic stem and progenitor cells are generated in a number of distinct locations during mammalian embryogenesis. These stem and progenitor cells migrate to a variety of anatomical locations through the conceptus until finally homing to the bone marrow shortly before birth. Under stress, extramedullary haematopoiesis can take place in regions that are typically lacking in blood-producing activity. Our aim in this review is to examine blood production throughout the embryo and adult, under normal and pathological conditions, to identify commonalities and distinctions between each niche. A clearer understanding of the mechanism underlying each haematopoietic niche can be applied to improving ex vivo cultures of haematopoietic stem cells and potentially lead to new directions for transplantation medicine.