The risk of emboli forming in AF depends on other risk factors such as age,  hypertension ,  diabetes , recent heart failure, or previous stroke.
Thrombus formation can also take place within the  ventricles , and it occurs in approximately 30% of anterior-wall  myocardial infarctions , compared with only 5% of inferior ones. Some other risk factors are poor ejection fraction (<35%), size of infarct, and the presence of AF. In the first three months after infarction, left-ventricle  aneurysms  have a 10% risk of emboli forming. Patients with  prosthetic  valves also carry a significant increase in risk of thromboembolism. Risk varies, based on the valve type (bioprosthetic or mechanical); the position (mitral or aortic); and the presence of other factors such as AF, left-ventricular dysfunction, and previous emboli [ citation needed ] .


Emboli often have more serious consequences when they occur in the so-called "end circulation": areas of the body that have no redundant blood supply, such as the brain and  heart . [ citation needed ]


Assuming a normal circulation, an embolus formed in a systemic  vein  will always impact in the lungs, after passing through the right side of the heart. This will form a  pulmonary embolism  that will result in a blockage of the  main artery of the lung  and can be a complication of  deep-vein thrombosis . The most common sites of origin of pulmonary emboli are the  femoral  veins . The deep veins of the calf are the most common sites of actual thrombi. [ citation needed ]


In paradoxical embolism, also known as crossed embolism, an embolus from the veins crosses to the arterial blood system. This is generally found only with heart problems such as septal defects  (holes in the cardiac septum) between the atria or ventricles. The most common such abnormality is  patent foramen ovale , occurring in about 25% of the adult population, but here the defect functions as a valve which is normally closed, because pressure is slightly higher in the left side of the heart. Sometimes, for example if a patient coughs just when an embolus is passing, it might cross to the arterial system. [ citation needed ]


The direction of the embolus can be one of two types: [ citation needed ]


In anterograde embolism, the movement of emboli is in the direction of blood flow. In retrograde embolism, the emboli move in opposition to the blood flow direction; this is usually significant only in blood vessels with low pressure (veins) or with emboli of high weight. [ citation needed ]


The word  embolism  comes from the Greek ἐμβολισμός, meaning "interpressure". [ citation needed ]


An  embolus  ( / ˈ ɛ m b ə l ə s / ; [ 1 ]   pl. :  emboli ; from the Greek ἔμβολος "wedge", "plug") is an unattached mass that travels through the  bloodstream  and is capable of creating blockages. When an embolus occludes a blood vessel, it is called an  embolism  or embolic event. [ 2 ]  There are a number of different types of emboli, including  blood clots ,  cholesterol  plaque or crystals,  fat globules ,  gas bubbles , and  foreign bodies , which can result in different types of embolisms.


The term is distinct from  embolism  and  thromboembolism , which may be consequences of an embolus, as discussed below. [ 3 ]


The term was coined in 1848 by  Rudolf Virchow  as part of his foundational research into  blood clots . [ 4 ] [ 5 ]


The term embolus refers generally to any free-floating mass in the bloodstream. A related term is embolism, which describes the phenomenon of an embolus lodging in a vessel and creating a blockage. [ 2 ]  An embolism is technically a consequence of an embolus, but the terms are sometimes used interchangeably. [ 6 ]  Both emboli and embolisms are usually named according to their composite substance. [ citation needed ]


In contrast to emboli, which can cause occlusion at sites distant from their points of origin, there are also non-traveling blockages that develop locally from vascular trauma and inflammation or other epithelial pathology, such as  atheromata  and  thrombi . If these local blockages dislodge into circulation, they become emboli and if not broken down during circulation, may cause embolism(s). [ 3 ]  For example, a  thromboembolism  is the result of a thrombus that has broken off the interior of a blood vessel and caused a vessel blockage elsewhere in the circulation.


Details of embolism classification are discussed below.


The physical composition of the embolic material is the defining feature for classification, and this composition reflects the underlying pathophysiologic mechanism of the embolus' formation. Furthermore, different types of emboli result in different types of embolisms, each with distinct clinical characteristics.


In  thromboembolism , the thrombus (blood clot) from a blood vessel is completely or partially detached from the site of thrombosis (clot). The blood flow will then carry the embolus (via blood vessels) to various parts of the body where it can block the lumen (vessel cavity) and cause vessel obstruction or occlusion. The free-moving thrombus is called an embolus. [ 7 ]  A thrombus is always attached to the vessel wall and is never freely moving in the blood circulation. This is also the key difference for pathologists to determine the cause of a blood clot, either by thrombosis or by post-mortem blood clot. Vessel obstruction will then lead to different pathological issues such as blood  stasis  and  ischemia . However, not only thromboembolism will cause the obstruction of blood flow in vessels, but also any kind of embolism is capable of causing the same problem.


Fat embolism  usually occurs when endogenous (from sources within the organism) fat tissue escapes into the blood circulation. The usual cause of fat embolism is therefore the  fracture  of tubular bones (such as the  femur ), which will lead to the leakage of fat tissue within the bone marrow into ruptured vessels. There are also exogenous (from sources of external origin) causes such as intravenous injection of  emulsions .


An  air embolism , on the other hand, is usually always caused by exogenic factors. This can be the rupture of  alveoli , and inhaled air can be leaked into the blood vessels. Other more-common causes include the puncture of the  subclavian vein  by accident or during operation where there is negative pressure. Air is then sucked into the veins by the negative pressure caused by thoracic expansion during the inhalation phase of respiration. Air embolism can also happen during intravenous therapy, when air is leaked into the system (however this  iatrogenic  error in modern medicine is extremely rare).


Gas embolism  is a common concern for deep-sea divers because the gases in human blood (usually nitrogen and helium) can be easily dissolved at higher amounts during the descent into deep sea. However, when the diver ascends to the normal atmospheric pressure, the gases become insoluble, causing the formation of small bubbles in the blood. This is also known as  decompression sickness  or the bends. This phenomenon is explained by  Henry's Law  in physical chemistry.


Embolism by  other materials  is rare.  Septic embolism  happens when a purulent tissue ( pus -containing tissue) is dislodged from its original focus.  Tissue embolism  is a near-equivalent to  cancer   metastasis , which happens when cancer tissue infiltrates blood vessels, and small fragments of them are released into the blood stream.  Foreign-body embolism  happens when exogenous—and only exogenous—materials such as  talc  enter the blood stream and cause occlusion or obstruction of blood circulation.   Bullet  embolism occurs in approximately 0.3% cases of  gunshot wounds . [ 8 ]   Amniotic-fluid embolism  is a rare complication of childbirth.


Emboli are clinically significant for their capacity to cause embolisms, which are a major cause of morbidity and mortality. [ 9 ] [ 10 ]  By themselves, emboli are pathologic and therefore indicate some underlying dysfunction.


It may be difficult in the clinical setting to differentiate a thrombotic event (i.e., a local clot at the site of symptoms) from an embolic event (i.e., local obstruction due to a free-floating mass that traveled through circulation from elsewhere in the body).


Septic emboli may also be a contributor to spreading infection through the bloodstream to other tissues. [ 11 ]


Rudolf Virchow , the German physician and "father of pathology", is generally credited with the first explanation of the relationship between thrombi, emboli, and embolisms. He coined the terms embolism (initially called "Embolia") and thrombosis while proposing a hypothesis for the pathophysiology of pulmonary thromboembolism. [ 5 ] [ 12 ]


In his work, he described the consequences of thrombosis and the factors leading thereto, a concept which today is known as  Virchow's Triad . However, there is some dispute regarding certain aspects of this attribution. [ 13 ]


Endothelial cell anergy  is a condition during the process of  angiogenesis , [ 2 ]  where  endothelial cells , the cells that line the inside of blood vessels, can no longer respond to  inflammatory cytokines . [ 3 ] [ 4 ]  These cytokines are necessary to induce the expression of  cell adhesion molecules  to allow  leukocyte  infiltration from the blood into the tissue at places of  inflammation , such as a tumor. This condition, which protects the tumor from the immune system, is the result of exposure to angiogenic growth factors.


Next to endothelial cell anergy, there are more vascular mechanisms that contribute to escape from immunity, such as the expression of  immune checkpoint  molecules (e.g.  PD-L1 /2) and proteins that can deliver death signals in leukocytes ( Fas ligand  and  galectin-1 ).


The formation of a leukocyte infiltrate at places of inflammation is dependent on the interaction of leukocytes in the blood with the vascular wall. This interaction and  leukocyte extravasation  is mediated by  cell adhesion molecules  on both leukocytes and  endothelium . The endothelial cells normally express low levels of adhesion molecules, but at places of inflammation these adhesion molecules become expressed due to the exposure to inflammatory cytokines, such as interleukin 1,  interferon gamma  and  tumor necrosis factor  alpha.


Endothelial cell anergy was first described in 1996 when it was shown that endothelial cells in a tumor are not able to upregulate the expression of adhesion molecules, such as  intercellular adhesion molecule-1  (ICAM-1, CD54),  vascular cell adhesion molecule-1  (VCAM-1, CD106) and  E-selectin  (CD62E), as a result from exposure angiogenic stimulation by e.g.  vascular endothelial growth factor  (VEGF) or fibroblast growth factor (FGF). [ 3 ] [ 4 ]  The result of endothelial cell anergy in a tumor is that leukocytes will not be able to reach the tumor, resulting in hampering of the anti-tumor immune response. Next to induction of endothelial cell anergy, ongoing angiogenesis is immunosuppressive at multiple levels. [ 5 ]


Since this form of immune suppression is mediated by angiogenic stimulation, it was shown that anti-angiogenic therapy could revert endothelial cell anergy, allow leukocytes to infiltrate tumors and stimulate anti-tumor immunity. [ 6 ] [ 7 ]  Overcoming endothelial cell anergy underlies the current success of clinical treatment of cancer with a combination of anti-angiogenic therapy and immunotherapy, mainly  immune checkpoint blockade . [ 8 ] [ 1 ]


It has been suggested that endothelial cell anergy also occurs during embryonic stages to allow efficient development of the  embryo  under immune silent conditions and help protecting the embryo from the  maternal immune response . Tumors have hijacked this process to grow under the support of endothelial cell anergy mediated immune suppression. [ 9 ]


The concept of endothelial cell anergy was introduced by Griffioen and coworkers in 1996. [ 1 ]


Endovascular and hybrid trauma and bleeding management   is a new and rapidly evolving concept within medical healthcare and endovascular  resuscitation . It involves early multidisciplinary evaluation and management of hemodynamically unstable patients with traumatic injuries as well as being a bridge to definitive treatment. [ 1 ] [ 2 ] [ 3 ]  It has recently been shown that the EVTM concept may also be applied to non-traumatic hemodynamically unstable patients. [ 4 ]


The fundamental principles of  trauma care  are built around  advanced trauma life support  (ATLS) guidelines using the mnemonic  ABCDE  for early assessment of the patient and detection of airway and circulatory problems. This way, life-threatening conditions are identified and resuscitation may be initiated, despite the lack of definitive diagnosis. [ 5 ]  The EVTM concept of acute trauma care incorporates modern endovascular techniques and procedures as additional adjuncts to this well-established protocol. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  The new suggested algorithm of  A ABCDE has emerged for EVTM enabled providers. The additional “A” stands for  A ccess, indicating the importance of gaining early vascular access to the  femoral artery  (and  vein ), and is fundamental to this concept of trauma care. [ 6 ]  As with traditional trauma care, vascular access in the peripheral or central veins allows for blood sampling and administration of drugs or fluids. However, for EVTM enabled providers, early femoral arterial access provides the possibility to use potentially lifesaving endovascular diagnostic and therapeutic tools for temporary management and bridge to definitive endovascular or open surgical treatment, in addition to arterial blood sampling and invasive blood pressure monitoring. [ 1 ] [ 7 ]


One of the major elements of EVTM is the multidisciplinary team approach. By combining the expertise present allows for optimal treatment not just at the time of patient arrival but also in the pre-hospital setting and later in the operating suite. It is all about teamwork with a common goal, to save the patient. It allows for the hybrid use of open surgery and endovascular methods for hemorrhage control and definitive treatment. In a hemodynamically unstable bleeding patient, traditional treatment is  laparotomy  with abdominal packing, but an EVTM team might simultaneously gain vascular access and perform REBOA for proximal control or embolization as a part in definitive treatment. An EVTM multidisciplinary approach requires complete transparency, good communication and leadership. It is however also important to remember that just because you can, doesn't mean that you should use an EVTM approach. EVTM should always be considered but only used in the optimally selected patient at the right time if the expertise and equipment is present to do it safely. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 8 ]


In the acute setting, the femoral artery is most often the easiest to identify and access thanks to its typically reasonable size. This is however obviously relative to individual anatomical differences and hemodynamic state of the patient. It is in general beneficial to gain early vascular access as the inguinal area is seldom occupied and, if possible, attempt to do this on the contralateral side to a major lower extremity injury. Access may be attempted by ultrasound-guided or blind puncture and surgical cut-down, where ultrasound-guided is the safest and most reasonable alternative for the less experienced. Vascular access is based on the  Seldinger technique . After puncturing the vessel with a needle and confirmation of arterial access a wire is advanced, the needle removed and a vascular sheath is introduced. The access is then ready to use. [ 6 ]


The use of endovascular modalities for bleeding control and treatment on hemodynamically unstable trauma patients is increasing. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) for hemorrhage control, angioembolization and stent grafts are highly established tools used for both arterial and venous hemorrhage in both traumatic and non-traumatic patients. [ 4 ] [ 9 ] [ 10 ] [ 11 ]  To be able to provide an endovascular opportunity for resuscitation requires good organization and a well-established endovascular team. [ 2 ] [ 3 ]


Acute care of a hemodynamically unstable trauma patient is never an ideal task. [ 12 ] [ 13 ]  The emphasis is on stopping blood extravasation and hemodynamic stabilisation without delay, despite if it is pre-hospital, in the emergency department or in a hybrid operating suite. REBOA, also called Aortic Balloon Occlusion (ABO), is a powerful endovascular tool that inflates an intra-aortic balloon occluding the lumen of the vessel and decreased or completely prevents blood flow to the more distal parts. If inflated in the aorta proximal to the identified source of bleeding it may help to diminish or stop blood extravasation, also potentially aiding to increase cardiac afterload. This should increase the central pressure and secure adequate myocardial and cerebral perfusion, hopefully rendering the patient, at least temporarily, more hemodynamically stable. REBOA is used as an endovascular tool for hemodynamic control and as a resuscitation adjunct that may prolong the life of the critical patient. REBOA is not only used from an endovascular resuscitation aspect, but may also to help by allowing more time for definitive treatment. [ 6 ] [ 9 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ excessive citations ]


Embolization  is a minimally invasive technique used in EVTM of selected hemodynamically unstable patients with both  traumatic  and non-traumatic injuries. It is the artificial creation of a thrombus by the introduction of various substances to intentionally occlude a vessel with the aim to stop or diminish blood extravasation and is a critical part of the modern management of arterial injuries. [ 6 ] [ 19 ]


Stent grafts , or endo-grafts, are a more permanent solution in the hemodynamically unstable patient and are an important part of the tool kit for EVTM. They are self-expanding artificial reconstructions of vessels with fabric coating deployed inside the original vessel and help to gain temporary control, stop the hemorrhage and repair the damaged vessel wall. They can be used and positioned, by an experienced surgeon, in every major vessel in the body. [ 6 ] [ 11 ] [ 20 ] [ 21 ] [ 22 ]


The  Journal of Endovascular Resuscitation and Trauma Management  (JEVTM) is an open access platform for publishing  peer-reviewed research  regarding endovascular hybrid hemorrhage control. The first issue was published August 2017 with continued publications quarterly. The editorial board is made up by clinicians and scientists who are experts within the field. [ 7 ]


In  hematology ,  erythrocyte deformability  refers to the ability of  erythrocytes  (red blood cells, RBCs) to change shape under a given level of applied  stress  without  hemolysing  (rupturing). This is an important property because erythrocytes must change their shape extensively under the influence of mechanical forces in  fluid flow  or while passing through  microcirculation  (see  hemodynamics ). The extent and  geometry  of this shape change can be affected by the mechanical properties of the erythrocytes, the magnitude of the applied forces, and the orientation of erythrocytes with the applied forces.  Deformability  is an intrinsic cellular property of erythrocytes determined by geometric and material properties of the  cell membrane , [ 1 ]  although as with many measurable properties the ambient conditions may also be relevant factors in any given measurement. No other cells of  mammalian  organisms have deformability comparable with erythrocytes; furthermore, non-mammalian erythrocytes are not deformable to an extent comparable with mammalian erythrocytes. In human RBCs there are structural supports that aid resilience, which include the  cytoskeleton :  actin  and  spectrin  that are held together by  ankyrin .


Shape change of erythrocytes under applied forces (i.e., shear forces in blood flow) is reversible and the biconcave-discoid shape, which is normal for most mammals, is maintained after the removal of the deforming forces. In other words, erythrocytes behave like  elastic  bodies, while they also resist to shape change under deforming forces. This viscoelastic behavior of erythrocytes is determined by the following three properties: [ 2 ]  1) Geometry of erythrocytes; the biconcave-discoid shape provides an extra surface area for the cell, enabling shape change without increasing surface area. This type of shape change requires significantly smaller forces than those required for shape change with surface area expansion. 2) Cytoplasmic viscosity; reflecting the  cytoplasmic   hemoglobin  concentration of erythrocytes. 3) Visco-elastic properties of erythrocyte membrane, mainly determined by the special membrane skeletal network of erythrocytes. [ citation needed ]


Erythrocyte deformability is an important determinant of blood viscosity, hence blood flow resistance in the vascular system. [ 3 ]  It affects blood flow in large blood vessels, due to the increased frictional resistance between fluid laminae under laminar flow conditions. It also affects the microcirculatory blood flow significantly, where erythrocytes are forced to pass through blood vessels with diameters smaller than their size. [ citation needed ]


Erythrocyte deformability is altered under various  pathophysiological  conditions.  Sickle-cell disease  is characterized by extensive impairment in erythrocyte deformability, being dependent on the  oxygen   partial pressure . Erythrocyte deformability has also been demonstrated to be impaired in  diabetes , peripheral  vascular  diseases,  sepsis  and a variety of other diseases.  The property offers broad utility in disease diagnosis [ 4 ]  (also see  Measurement , below).


Stored packed red blood cells (sometimes denoted "pRBC" or "StRBC") also experience changes in membrane properties like deformability during storage and related processing, as part of a broader phenomenon known as "storage lesion." While the clinical implications are still being explored, deformability can be indicative of quality or preservation thereof for stored RBC product available for  blood transfusion . [ 5 ] [ 6 ] [ 7 ]   Perfusion (or perfusability) is a deformability-based metric that may offer a particularly physiologically-relevant representation of storage-induced deterioration of RBC occurring in  blood banks , and the associated impacts of storage conditions/systems. [ 8 ]


Erythocyte deformability is a measurable property, and various means for its measurement have been explored - with each having results and significance being highly particularized to the given approach employed. Accordingly, the term is somewhat loose in the sense that a given cell or sample of cells may be deemed significantly more "deformable" by one means/metric relative to another means/metric. Thus for meaningful "apples-to-apples" comparisons involving cell deformability, it is important to utilize the same qualitative approach. [ citation needed ]


Ektacytometry  based on  laser diffraction analysis  is a commonly preferred (and a fairly direct) method for measuring deformability. [ 9 ]   Another direct metric is  optical tweezers , which targets individual cells.  Deformability can in effect be measured indirectly, such as by how much pressure and/or time it takes cells pass through pores of a filter (i.e.,  filterability  or filtration) [ 10 ]  or perfuse through capillaries ( perfusion ), [ 11 ]   in vitro  or  in vivo , having smaller diameters than the cells'.  Some deformability tests may be more physiologically-relevant than others for given applications. For example, perfusion is more sensitive to relatively small changes in deformability (compared to filterability), [ 12 ]  thus making it preferable for assessing RBC deformability in contexts where microcirculatory implications are of particular interest.  Moreover, some tests may track how deformability itself changes as conditions change and/or as deformation is repeated. [ citation needed ]


Erythrocytes/RBC may also be tested for other (related) membrane properties, including  erythrocyte fragility  (osmotic or mechanical) and cell morphology.  Morphology can be measured by indexes which characterize shape changes of differences among cells.  Fragility testing involves subjecting a sample of cells to osmotic and/or mechanical stress(es), then ascertaining how much hemolysis results thereafter, and then characterizing susceptibility to or propensity for stress-induced hemolysis with an index or profile (which can be useful to assess cells' ability to withstand sustained or repeated stresses). [ citation needed ]


Other related red blood cell properties can include adhesion and aggregation, which along with deformability are often classed as RBC "flow properties."


NM_152521 NM_001291832


Erythroferrone  is a protein hormone encoded in humans by the  ERFE  gene.  Erythroferrone is produced by  erythroblasts , inhibits the production of  hepcidin  in the liver, and so increases the amount of  iron  available for  hemoglobin  synthesis. [ 5 ] [ 6 ]  Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis. [ 7 ]


It was identified in 2014 in mice where the transcript was found in  bone marrow , encoded by the mouse  Fam132b  gene. [ 6 ]   The homologous gene in humans is  FAM132B  and the sequence is conserved in other species. The protein is synthesized by erythroblasts and secreted. [ 6 ]   This sequence had previously been found expressed in mouse skeletal muscle, called  myonectin  (CTRP15), and linked to lipid homeostasis. [ 8 ]


Seldin and his colleagues have written: "Myonectin is expressed and secreted predominantly by skeletal muscle.... (Our) results suggest that myonectin is a nutrient-responsive metabolic regulator secreted by skeletal muscle in response to changes in cellular energy state resulting from glucose or fatty acid fluxes. Many metabolically relevant secreted proteins (e.g.  adiponectin ,  leptin ,  resistin , and  RBP ) and the signaling pathways they regulate in tissues are known to be dysregulated in the condition of obesity. The reduction in expression and circulating levels of myonectin in the obese state may represent yet another component of the complex metabolic circuitry dysregulated by excess caloric intake. Although exercise has long been known to have profound positive impacts on systemic insulin sensitivity and energy balance, the underlying mechanisms remain incompletely understood. That voluntary exercise dramatically increases the expression and circulating levels of myonectin to promote fatty acid uptake into cells may underlie one of the beneficial effects of physical exercise." [ 9 ]


Myonectin was shown in 2015 to be identical to erythroferrone, a hormone produced in erythroblasts that is involved in iron metabolism. [ 5 ] > [ 6 ]


Erythroferrone in humans is transcribed as a  precursor  of 354 amino acids, with a  signal peptide  of 28 amino acids.  The mouse gene encodes a 340 amino acid protein which is 71% identical. [ 6 ]   Homology is greater at the C-terminal where there is a  TNF-alpha -like domain. [ 10 ]  As a member of the C1q/TNF-Related Protein ( CTRP ) family, erythroferrone has a 4-domain structure with a unique N-terminus. The two larger domains are connected by a short, proline-rich, collagenous linker that is thought to promote protein multimerization. Erythroferrone is predicted to contain two PCSK3/ furin  recognition sites. The protein hormone weighs approximately 35-40  kDa . [ 11 ]


Erythroferrone is a hormone that regulates  iron metabolism  through its actions on hepcidin. [ 5 ]   As shown in mice and humans, it is produced in erythroblasts, which proliferate when new red cells are synthesized, such as after hemorrhage when more iron is needed (so-called stress  erythropoiesis ). [ 12 ]   This process is governed by the renal hormone,  erythropoietin . [ 6 ]


Its mechanism of action is to inhibit the expression of the liver hormone, hepcidin. [ 12 ]   This process is governed by the renal hormone,  erythropoietin . [ 6 ]   By suppressing hepcidin, ERFE increases the function of the cellular iron export channel,  ferroportin .  This then results in increased iron absorption from the  intestine  and mobilization of iron from stores, which can then be used in the synthesis of  hemoglobin  in new  red blood cells . [ 6 ]  Erythroferrone inhibits hepcidin synthesis by binding bone morphogenetic proteins and thereby inhibiting the bone morphogenetic protein pathway that controls hepcidin expression. [ 13 ] [ 14 ]


Mice deficient in the gene encoding erythroferrone have transient maturational hemoglobin deficits and impaired hepcidin suppression in response to phlebotomy with a delayed recovery from  anemia . [ 6 ]


In its role as myonectin, it also promotes lipid uptake into adipocytes and hepatocytes. [ 8 ]


Synthesis of erythroferrone is stimulated by erythropoietin binding to its receptor and activating the  Jak2 / Stat5  signaling pathway. [ 6 ]


The clinical significance in humans is becoming clear. [ 15 ]   From parallels in the mouse studies, there may be diseases where its function could be relevant.  In a mouse model of  thalassemia , its expression is increased, resulting in  iron overload , which is also a feature of the human disease. [ 16 ]   A role in the recovery from the  anemia of inflammation  in mice has been shown [ 17 ]  and involvement in inherited anemias with ineffective erythropoiesis, anemia of chronic kidney diseases and iron-refractory iron-deficiency anemia has been suggested. [ 6 ] [ 15 ]


Erythroferrone levels in blood have been shown by immunoassay to be higher after blood loss or  erythropoetin  administration. Patients with  beta-thalassemia  have very high levels, and these decrease after  blood transfusion . [ 18 ]


Faggot cells  are cells normally found in the hypergranular form of  acute promyelocytic leukemia  (FAB - M3). These promyelocytes (not blast cells) have numerous  Auer rods  in the  cytoplasm  which gives the appearance of a  bundle of sticks , from which the cells are given their name. [ 1 ] [ 2 ]


Ferroportin-1 , also known as  solute carrier family 40 member 1 (SLC40A1)  or  iron-regulated transporter 1 (IREG1) , is a  protein  that in humans is encoded by the  SLC40A1   gene . [ 5 ]  Ferroportin is a  transmembrane protein  that transports  iron  from the inside of a  cell  to the outside of the cell. Ferroportin is the only known iron exporter. [ 6 ]


After dietary iron is absorbed into the cells of the small intestine, ferroportin allows that iron to be transported out of those cells and into the bloodstream. Fpn also mediates the efflux of iron recycled from macrophages resident in the spleen and liver. [ 7 ]


Ferroportin is regulated by hepcidin, a hormone produced by the liver;  hepcidin  binds to Fpn and limits its iron-efflux activity, thereby reducing iron delivery to the blood plasma. [ 8 ]  Therefore, the interaction between Fpn and hepcidin controls systemic  iron homeostasis .


Members of the ferroportin family consist of 400-800  amino acid  residues, [ 9 ]  with a  highly conserved   histidine  at residue position 32 (H32), and exhibit 8-12 putative  transmembrane domains . Human Fpn consists of 571 amino acid residues. [ 9 ]  When H32 is mutated in mice, iron transport activity is impaired. [ 10 ]


Recent crystal structures generated from a bacterial  homologue  of ferroportin (from  Bdellovibrio bacteriovorus ) revealed that the Fpn structure resembles that of  major facilitator superfamily  (MFS) transporters. [ 11 ] [ 12 ]  The prospective substrate binding site is located at the interface between the  N-terminal  and  C-terminal  halves of the protein, and is alternately accessible from either side of the cell membrane, [ 12 ]  consistent with MFS transporters.


Ferroportin-mediated iron efflux is  calcium -activated; studies of human Fpn expressed in  Xenopus laevis  oocytes demonstrated that calcium is a required  cofactor  for Fpn, but that Fpn does not transport calcium. [ 12 ]  Thus, Fpn does not function as an iron/calcium antiporter. The thermodynamic driving force for Fpn remains unknown.


In addition to iron, human ferroportin has been shown to transport  cobalt ,  zinc , [ 13 ]  and  nickel . [ 12 ]  Ferroportin may also function as a  manganese  exporter. [ 14 ]


Ferroportin is found on the basolateral membranes of intestinal epithelia of mammals, including: [ 15 ] [ 16 ]


Ferroportin-1 plays an important role in  neural tube  closure and  forebrain  patterning. [ 17 ]  Mouse embryos lacking the  Slc40a1  gene are aborted before  gastrulation  occurs, suggesting that the Fpn1 protein encoded is necessary and essential for normal embryonic development. [ 15 ]  Fpn1 is expressed in the  syncytiotrophoblast  cells in the placenta and visceral  endoderm  of mice at E7.5. [ 5 ] [ 15 ]  Further, several retrospective studies have noted an increased incidence of  spina bifida  occurring after low maternal intake of iron during embryonic and fetal development. [ 18 ] [ 19 ]


A study examining the consequences of several different mutations of the  Slc40a1  mouse gene suggested that several serious neural tube and patterning defects were produced as a result, including spina bifida,  exencephaly , and forebrain truncations, among others. [ 17 ]  Given the findings of studies to date, there appears to be significant evidence that intact iron transport mechanisms are critical to normal neural tube closure. Furthermore, other experiments have suggested that  Fpn1  product and activity is required along the entire anterior-posterior axis of the animal to ensure proper closure of the neural tube. [ 17 ]


It is known that ferroportin (SLC40A1) gene is expressed at a low level in infertile women. Its mRNA levels were discovered to be down-regulated in these women, specifically in  granulosa cells . What's more, low expression of ferroportin is also associated with infertility when some features like age and smoking habits are considered.
It is also important to mention that, not only is ferroportin down-regulated in granulosa cells, but also in cervical cells of infertile women, and that the association between infertility and low ferroportin levels in these cells can be seen, again, when mRNA ferroportin levels was adjusted by age and smoking status. [ 20 ]


Ferroportin is inhibited by hepcidin, which binds to ferroportin and internalizes it within the cell. [ 8 ]  This results in the retention of iron within  enterocytes ,  hepatocytes , and  macrophages  with a consequent reduction in iron levels within the blood serum. This is especially significant with enterocytes which, when shed at the end of their lifespan, results in significant iron loss. Hepcidin is synthesized in response to various cytokines, as described in the  Hepcidin  article, as well as in this article by Ganz. [ 21 ]


Ferroportin expression is also regulated by the  IRP  regulatory mechanism. If the iron concentration is too low, the IRP concentration increases, thus inhibiting the ferroportin translation and increasing intracellular iron and  ferritin  concentrations. The ferroportin translation is also down regulated post-transcriptionally by the micro RNA miR-485-3p, which is produced in response to iron deficiency. [ 22 ]


Mutations in the ferroportin gene are known to cause an autosomal dominant form of iron overload known as  Hemochromatosis type 4   or Ferroportin Disease. The effects of the mutations are generally not severe but a spectrum of clinical outcomes are seen with different mutations. Ferroportin is also associated with  African iron overload . Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis.


Ferroportin is part of the  ferroportin (Fpn) family . Members of the family are found across eukaryotes in animals and plants as well as in  Proteobacteria , a group of bacteria. [ 23 ]


As of  this edit , this article uses content from  "2.A.100 The Ferroportin (Fpn) Family" , which is licensed in a way that permits reuse under the  Creative Commons Attribution-ShareAlike 3.0 Unported License , but not under the  GFDL . All relevant terms must be followed.


Gestational (incidental) thrombocytopenia  is a condition that commonly affects pregnant women.  Thrombocytopenia  is defined as the drop in  platelet  count from the normal range of 150,000–400,000/μL to a count lower than 150,000/μL. [ 1 ]  There is still ongoing research to determine the reason for the lowering of platelet count in women with a normal pregnancy. Some researchers speculate the cause to be dependent on dilution, decreased production of platelets, or an increased turnover event. [ 2 ]  Although women with normal pregnancy experience a low platelet count, women experiencing a continuous drop in platelet will be diagnosed with thrombocytopenia and women with levels greater than 70,000/μL will be diagnosed with gestational thrombocytopenia. [ 2 ]


Thrombocytopenia affects approximately 7–10% of pregnant women and of the 7–10%, within that population; approximately 70–80% have gestational thrombocytopenia  [ 3 ]


Gestational thrombocytopenia is a disorder similar to  immune thrombocytopenia  (ITP) and is difficult to differentiate between the two disorders. [ 2 ]  Therefore, a medical history is conducted to because a diagnostic test is unavailable. [ 2 ]


Although there are no alarming symptoms related to gestational thrombocytopenia, an individual with thrombocytopenia might show the following symptoms [ 4 ]  –


It is evident that there is a decrease in platelet count during pregnancy; however, the cause of the decrease is unknown. [ 2 ]   However researchers theorize that the decrease in platelet count is due to the decreased production of platelets and/or increased destruction of platelets. [ 4 ]


Generally, there is a decrease in  platelet  count in pregnant women and it will be due to many reasons. [ 1 ]  The two main causes of thrombocytopenia are a decrease in the production of platelets in the  bone marrow  and an increase in the destruction of the platelets. [ 4 ]  Platelets, along with other components of the blood, are produced in the spongy tissue found in the bone, known as bone marrow. [ medical citation needed ]   Low platelet count maybe due to the decreased production of platelets in the bone marrow. A decreased production would be due to vitamin B12 deficiency, iron deficiency,  aplastic anemia , viral infections,  chemotherapy , alcohol consumption,  leukemia ,  myelodysplasia , and  cirrhosis . [ medical citation needed ]  During pregnancy, the fetus’ waste products diffuse into the mother’s sinuses (blood stream), and cause the mother's  spleen  to become overactive and enlarged. [ 5 ]  Normally, the spleen filters and removes the waste products and with the overload of unwanted substances in the bloodstream, the spleen will remove blood cells too quickly  [ 5 ]  or store the platelets. [ 4 ]   In both cases, the overactive spleen would cause a decrease in the circulation of the platelets. [ 4 ]


Gestational thrombocytopenia will become evident during the mid-second trimester through the third trimester of pregnancy and it is diagnosed based on exclusion. [ 2 ]  For example, women with a history of immune thrombocytopenia or thrombocytopenia, prior to pregnancy, will not be diagnosed with gestational thrombocytopenia. [ 2 ]


Patients with low platelet counts, lower than 70,000/μL, will be difficult to diagnose because low platelet counts maybe due to gestational thrombocytopenia or immune thrombocytopenia. [ 6 ]   In such cases, a treatment of immune thrombocytopenia therapy (corticosteroids, or intravenous immunoglobulin) will be instructed. [ 6 ]  If there is an improvement in the platelet levels, the patient will be diagnosed with immune thrombocytopenia, and if not the patient will be diagnosed with severe gestational thrombocytopenia [ 2 ]


In order for the physician to  determine the underlying cause of the gestational thrombocytopenia, the following tests are conducted:


During routine prenatal checkups, the physician will conduct a complete blood count test to determine the components of blood. The complete blood count will provide further information about platelet levels.


The physician may conduct an ultrasound around the spleen to determine if the spleen is enlarged. [ medical citation needed ]


The physician may conduct a bone marrow aspiration or bone marrow biopsy, if there is a decreased production of platelets in the bone marrow. [ medical citation needed ]  A bone marrow aspiration and bone marrow biopsy may be conducted at the same time.


There is no known information regarding the prevention of this disorder. [ citation needed ]  There is no known information regarding the group of women who are likely to be diagnosed with this disorder. [ citation needed ]


Women, diagnosed with gestational thrombocytopenia, will have their complete blood test conducted during each pre-natal visit and monitored by the doctor. [ 6 ]  Having diagnosed gestational thrombocytopenia, women should continue their normal activities because the diagnosis does not change the management of pregnancy. [ 6 ]  Also, the diagnosis of gestational thrombocytopenia poses no harm or risk to the mother or the fetus. [ 7 ]  There are no diagnostic tests available for gestational thrombocytopenia; rather it is diagnosed based on exclusion. [ 6 ]   Women who have a history of immune thrombocytopenia or thrombocytopenia prior to becoming pregnant would not be diagnosed with gestational thrombocytopenia [ 6 ]


Women who have platelet levels lower than 70,000 / μL, during pregnancy, maybe experiencing severe gestational thrombocytopenia or immune thrombocytopenia. [ 6 ]   In such cases, if the treatment of immune thrombocytopenia therapy (corticosteroids, or intravenous immunoglobulin) [ 2 ]   does not improve the platelet count, the patient will be diagnosed with severe gestational thrombocytopenia. [ 2 ]  Severe gestational thrombocytopenia may pose a risk for complications with the use of epidural or general anesthesia during delivery. [ 6 ]


Those who have no previous history of thrombocytopenia, besides the occurrence in previous pregnancies (gestational thrombocytopenia), the platelet levels will go back to a normal range 1–2 months after the delivery. [ 6 ]  Post delivery, approximately 1–3 months later, women with gestational thrombocytopenia should have a complete blood test conducted. [ 6 ]  Lastly, gestational thrombocytopenia is a disorder that may reoccur in future pregnancies  [ 3 ]


A history of this disorder has not yet been established.


The  Haldane effect  is a property of  hemoglobin  first described by  John Scott Haldane , within which oxygenation of blood in the lungs displaces carbon dioxide from hemoglobin, increasing the removal of carbon dioxide. Consequently, oxygenated blood has a reduced affinity for carbon dioxide. Thus, the Haldane effect describes the ability of hemoglobin to carry increased amounts of carbon dioxide (CO 2 ) in the deoxygenated state as opposed to the oxygenated state. Vice versa, it is true that a high concentration of CO 2  facilitates dissociation of oxyhemoglobin, though this is the result of two distinct processes (Bohr effect and Margaria-Green effect) and should be distinguished from Haldane effect.


Carbon dioxide travels through the  blood  in three different ways. One of these ways is by binding to  amino  groups, creating  carbamino  compounds. Amino groups are available for binding at the N-terminals and at side-chains of  arginine  and  lysine  residues in hemoglobin. When carbon dioxide binds to these residues  carbaminohemoglobin  is formed. [ 1 ]  This amount of  carbaminohemoglobin  formed is inversely proportional to the amount of oxygen attached to hemoglobin. Thus, at lower oxygen saturation, more  carbaminohemoglobin  is formed. These dynamics explain the relative difference in hemoglobin's affinity for carbon dioxide depending on oxygen levels known as the Haldane effect. [ 2 ]


Histidine  residues in hemoglobin can accept protons and act as  buffers . Deoxygenated hemoglobin is a better  proton acceptor  than the oxygenated form. [ 1 ]


In red blood cells, the enzyme  carbonic anhydrase  catalyzes the conversion of dissolved carbon dioxide to  carbonic acid , which rapidly dissociates to  bicarbonate  and a free  proton :


By  Le Chatelier's principle , anything that stabilizes the proton produced will cause the reaction to shift to the right, thus the enhanced affinity of deoxyhemoglobin for protons enhances synthesis of bicarbonate and accordingly increases capacity of deoxygenated blood for carbon dioxide. The majority of carbon dioxide in the blood is in the form of bicarbonate. Only a very small amount is actually dissolved as carbon dioxide, and the remaining amount of carbon dioxide is bound to hemoglobin.


In addition to enhancing removal of carbon dioxide from oxygen-consuming tissues, the Haldane effect promotes dissociation of  carbon dioxide  from hemoglobin in the presence of  oxygen . In the oxygen-rich capillaries of the lung, this property causes the displacement of carbon dioxide to plasma as low-oxygen blood enters the  alveolus  and is vital for  alveolar gas exchange .


The general equation for the Haldane Effect is:


However, this equation is confusing as it reflects primarily the  Bohr effect . The significance of this equation lies in realizing that oxygenation of Hb promotes dissociation of H +  from Hb, which shifts the bicarbonate buffer equilibrium towards CO 2  formation; therefore, CO 2  is released from RBCs. [ 3 ]


In patients with lung disease, lungs may not be able to increase  alveolar ventilation  in the face of increased amounts of dissolved CO 2 .


This partially explains the observation that some patients with  emphysema  might have an increase in P a CO 2  (partial pressure of arterial dissolved carbon dioxide) following administration of supplemental oxygen even if content of CO 2  stays equal. [ 4 ]


The  Harrington–Hollingsworth experiment  was an  experiment  that established the  autoimmune  nature of the  blood disorder   immune thrombocytopenic purpura . [ 1 ] [ 2 ]  It was performed in 1950 by the academic staff of  Barnes-Jewish Hospital  in  St. Louis, Missouri . [ 2 ]


The experiment was undertaken in 1950 by William J. Harrington and  James W. Hollingsworth , who postulated that in patients with  idiopathic thrombocytopenic purpura  (ITP), it was a blood factor that caused the destruction of  platelets . [ 2 ]  To test this hypothesis, Harrington received 500 ml of blood from a patient with ITP. [ 2 ]  Within three hours, his platelets dropped to dangerously low levels and he experienced a  seizure . [ 2 ]  His platelet count remained extremely low for four days, finally returning to normal levels by the fifth day. [ 2 ]   Bone marrow biopsy  from Harrington's  sternum  demonstrated normal  megakaryocytes , the cells necessary for  platelet production . [ 2 ]


Subsequently the experiment was repeated on all suitable staff members at the Barnes-Jewish Hospital. All subjects developed low platelet counts within three hours, and all recovered after a period of several days. [ 2 ]


Schwartz notes that the Harrington–Hollingsworth experiment was a turning point in the understanding of ITP's pathophysiology:


The Harrington–Hollingsworth experiment changed the meaning of the "I" in ITP from idiopathic to immune, but "immune" in this case means "autoimmune," because the antibodies bind to and cause the destruction of the patient's own platelets. [ 2 ]


The experiment was the first to demonstrate that infusion of an ITP patient's plasma into a normal patient caused a precipitous drop in platelet count. [ 2 ]  This suggested that low platelet counts ( thrombocytopenia ) in patients with ITP was caused by a circulating factor found in the blood. [ 2 ]  Many studies performed since then have demonstrated that this circulating factor is in fact a collection of  immunoglobulins . [ 3 ] [ 4 ]
Many physician-scientists believe the findings had a major influence on the field of autoimmunity, which was not universally accepted at the time as a mechanism of human disease.


Hemagglutination , or  haemagglutination , is a specific form of  agglutination  that involves  red blood cells  (RBCs). It has two common uses in the laboratory: blood typing and the  quantification of virus  dilutions in a  haemagglutination assay .


Blood type can be determined by using  antibodies  that bind to the  A or B blood group   antigens  in a sample of blood.


For example, if antibodies that bind the A blood group are added and agglutination occurs, the blood is either type A or type AB. To determine between type A or type AB, antibodies that bind the B group are added and if agglutination does not occur, the blood is type A. If agglutination does not occur with either antibodies that bind to type A or type B antigens, then neither antigen is present on the blood cells, which means the blood is type O. [ 1 ] [ 2 ]


In blood grouping, the patient's serum is tested against RBCs of known blood groups and also the patient's RBCs are tested against known serum types. In this way the patient's blood group is confirmed from both RBCs and serum. A direct  Coombs test  is also done on the patient's blood sample in case there are any confounding antibodies.


Many viruses attach to molecules present on the surface of RBCs. A consequence of this is that at certain concentrations, a viral suspension may bind together (agglutinate) the RBCs, thus preventing them from settling out of suspension. Since agglutination is not linked to infectivity, attenuated viruses can therefore be used in  assays  while an additional assay such as a  plaque assay  must be used to determine infectivity. By serially diluting a virus suspension into an assay tray (a series of wells of uniform volume) and adding a standard amount of blood cells, an estimation of the number of virus particles can be made. While less accurate than a  plaque assay , it is cheaper and quicker (taking just 30 minutes). [ citation needed ]


This assay may be modified to include the addition of an antiserum. By using a standard amount of virus, a standard amount of blood cells, and serially diluting the  antiserum , one can identify the concentration of the antiserum (the greatest dilution which inhibits hemagglutination).


Hemagglutinins  (alternatively spelt  haemagglutinin , from the Greek  haima , 'blood' + Latin  gluten , 'glue') are homotrimeric  glycoproteins  present on the  protein capsids  of  viruses  in the  Paramyxoviridae  and  Orthomyxoviridae  families. [ 1 ] [ 2 ] [ 3 ]  Hemagglutinins are responsible for binding to  receptors ,  sialic acid residues , on host cell membranes to initiate virus docking and  infection . [ 4 ] [ 5 ]


Specifically, they recognize  cell-surface   glycoconjugates  containing sialic acid on the surface of host  red blood cells  with a low affinity and use them to enter the  endosome  of host cells. [ 6 ]  Hemagglutinins tend to recognize α-2,6-linked sialic acids of the host cells in humans and α-2,3-linked sialic acids in avian species, although there is evidence that hemagglutinin specificity can vary. This correlates to the fact that  Influenza A  typically establishes infections in the upper respiratory tract in humans, where many of these α-2,6-linked sialic acids are present. [ 7 ]  There are various subtypes of hemagglutinins, in which H1, H2, and H3 are known to have human susceptibility. [ 8 ]  It is the variation in hemagglutinin (and  neuraminidase ) subtypes that require health organizations (ex.  WHO ) to constantly update and surveil the known circulating flu viruses in human and animal populations (ex.  H5N1 ).


In the endosome, hemagglutinins undergo conformational changes due to a  pH  drop to of 5–6.5 enabling viral attachment through a fusion  peptide . [ 9 ]


Virologist  George K. Hirst  discovered agglutination and hemagglutinins in 1941. [ 10 ]   Alfred Gottschalk  proved in 1957 that hemagglutinins bind a  virus  to a host cell by attaching to  sialic acids  on  carbohydrate  side chains of  cell-membrane   glycoproteins  and  glycolipids . [ 11 ]


The name "hemagglutinin" comes from the  protein 's ability to cause red blood cells (erythrocytes) to clump together (" agglutinate ")  in vitro . [ 12 ]


Hemagglutinins are small proteins that extend from the surface of the virus membrane as spikes that are 135 Angstroms (Å) in length and 30-50 Å in diameter. [ 19 ]  Each spike is composed of three identical  monomer  subunits, making the protein a  homotrimer . These monomers are formed of two  glycopeptides , HA1 and HA2, and linked by two  disulphide   polypeptides , including membrane-distal HA1 and the smaller membrane-proximal HA2.  X-ray crystallography ,  NMR spectroscopy , and  cryo-electron microscopy  were used to solve the protein's structure, the majority of which is  α-helical . [ 20 ]  In addition to the homotrimeric core structure, hemagglutinins have four subdomains: the membrane-distal receptor binding R subdomain, the vestigial domain E, that functions as a receptor-destroying  esterase , the fusion domain F, and the membrane anchor subdomain M. The membrane anchor subdomain forms elastic protein chains linking the hemagglutinin to the  ectodomain . [ 21 ]


On the viral capsids of influenza types  A  and  B , hemagglutinin is initially inactive. Only when cleaved by host proteins, does each monomer polypeptide of the homotrimer transforms into a dimer – composed of HA1 and HA2 subunits attached by disulfide bridges. [ 22 ]  The HA1 subunit is responsible for docking the viral capsid onto the host cell by binding to sialic acid residues present on the surface of host respiratory cells. This binding triggers  endocytosis . [ 5 ]  The pH in the endosomal compartment then decreases from proton influx, and this causes a conformational change in HA that forces the HA2 subunit to “flip outward.” The HA2 subunit is responsible for membrane fusion. It binds to the endosomal membrane, pulling the viral capsid membrane and the endosomal membrane tightly together, eventually forming a pore through which the viral genome can enter into the host cell cytoplasm. [ 3 ]  From here, the virus can use host machinery to proliferate.


Hematidrosis , also called  hematohidrosis ,  haematidrosis ,  hemidrosis  and  blood sweat , is a very rare condition in which a human  sweats   blood . [ 1 ]  The term is from  Ancient Greek   haîma / haímatos  ( αἷμα / αἵματος ), meaning blood, and  hīdrṓs  ( ἱδρώς ), meaning sweat.


Blood usually oozes from the forehead, nails,  umbilicus , and other skin surfaces. In addition, oozing from  mucocutaneous  surfaces causing  nosebleeds , blood-stained tears, and vicarious menstruation are common. [ 2 ]  The episodes may be preceded by intense  headache  and abdominal pain and are usually self-limiting. In some conditions, the secreted fluid is more dilute and appears to be blood-tinged, while others may have darker, bright red secretions resembling blood. [ 3 ]


While the extent of blood loss generally is minimal, hematidrosis also results in the skin becoming extremely tender and fragile.


Hematidrosis is a condition in which  capillary  blood vessels that feed the  sweat glands  rupture, causing them to exude blood, occurring under conditions of extreme physical or emotional  stress . [ 4 ]  Severe mental  anxiety  activates the  sympathetic nervous system  to invoke the  fight-or-flight response  to such a degree as to cause hemorrhage of the vessels supplying the sweat glands. [ 5 ]  It has been suggested that acute fear and extreme stress can cause hematidrosis. [ 6 ]


Investigations such as  platelet  count, platelet aggregation test,  coagulation  profile, and  skin biopsy  reveal no abnormalities, and direct light microscopy of fluid demonstrates presence of normal  red blood cells . Investigations also fail to show any  vasculitis  or skin appendages (i.e.  sweat glands ,  sebaceous glands  and  hair follicles ) abnormalities. [ 3 ] [ 7 ]


A 2015 case study investigated hematidrosis with a patient who has  epilepsy . [ 8 ]


Effects on the body include weakness and mild-to-moderate dehydration from the severe anxiety and both blood and sweat loss. [ 9 ]


The condition is very rare, but there are reports in the medical literature of successful treatment with  beta blockers  ( propranolol  10 mg), [ 10 ] [ 11 ]  with significant reduction in the frequency of spontaneous blood oozing. The successful use of beta blockers supports the theory that the condition is induced by stress and anxiety. However, this etiology is not yet fully established, as the high prevalence of stress and anxiety in the modern era has not changed the incidence of this extremely rare disease, suggesting that other co-abnormalities also play a key role. [ 7 ]   Atropine  sulfate  transdermal patches  have also been used successfully. [ 3 ]


Favorable results with psychiatric counselling to reduce stress highlight the relationship between psychogenic causes and hematohidrosis. [ 5 ]


Dermatological research notes the presence of hematidrosis in people awaiting execution. [ 5 ]  It has also been proposed as a possible explanation for Jesus'  agony in the garden  of  Gethsemane  ( Luke 22:44 ), [ 12 ]  and for claims associated with  stigmata . [ 13 ] [ 14 ]


Leonardo da Vinci  described a soldier who sweated blood before battle. The phenomenon has also been observed in individuals in fear for their lives; a case occurred during the  London Blitz , and a case of fear of a storm while sailing, etc. [ 13 ]


Hematology analyzers  ( also spelled   haematology analysers  in  British English ) are used to count and identify blood cells at high speed with accuracy. [ 1 ] [ 2 ] [ 3 ]  During the 1950s, laboratory technicians counted each individual blood cell underneath a  microscope . Tedious and inconsistent, this was replaced with the first, very basic hematology analyzer, engineered by  Wallace H. Coulter . The  early hematology analyzers  relied on Coulter's principle (see  Coulter counter ). However, they have evolved to encompass numerous techniques. [ 4 ]


Hematology analyzers are used to conduct a  complete blood count  (CBC), which is usually the first test requested by physicians to determine a patient's general health status. [ 5 ]  A complete blood count includes  red blood cell  (RBC),  white blood cell  (WBC),  hemoglobin , and  platelet  counts, as well as  hematocrit  levels. Other analyses include:  [ citation needed ]


A 3-part differential cell counter uses Coulter's principle to find the size and volume of the cell. The sample is lysed and dissolved into an electrolyte solution in a container, which also holds a smaller container. The smaller container has two pumps running to and from its solution, one creating a vacuum and the other replacing the lost solution. The smaller container has a small hole (an orifice) near the bottom of the container. Coulter's principle is applied through the use of two electrodes. One electrode (the internal electrode) is within the smaller container, and the other (the external electrode) is outside of the smaller container but within the electrolyte/sample solution. As the vacuum draws the sample cells through the orifice, the cell momentarily causes electrical resistance to the current as it passes through the orifice. This resistance is recorded, measured, amplified, and processed which can then be interpreted by the computer into a histogram. The 3-part analyzer is able to differentiate between three types of white blood cells (WBCs):  neutrophils ,  lymphocytes , and  monocytes . [ 7 ]


This type of hematology analyzer utilizes both Coulter's principle and flow cytometry to determine the  granularity , diameter, and inner complexity of the cells. Using hydrodynamic focusing, the cells are sent through an aperture one cell at a time. During this, a laser is directed at them, and the scattered light is measured at multiple angles. The absorbance is also recorded. The cell can be identified based on the intensity of the scattered light and the level of absorbance. [ 8 ]  A 5-part cell counter can differentiate all WBC types (neutrophils, lymphocytes,  basophils ,  eosinophils , and monocytes). 5-part analyzers are more expensive than 3-part analyzers, but provide more in-depth information about the sample. Specific jobs, such as  allergy  testing, require 5-part differential analysis. However, most medical tasks can be completed with the 3-part analyzer. [ citation needed ]


The hematology analyzer is broken down into five key components: [ 9 ]


These are the major companies that are known to make quality Hematology Analyzers for hospitals and laboratories:  [ 10 ]


Hematopoietic stem-cell transplantation  ( HSCT ) is the  transplantation  of  multipotent hematopoietic stem cells , usually derived from  bone marrow ,  peripheral blood , or  umbilical cord blood , in order to replicate inside a patient and produce additional normal blood cells. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]  HSCT may be  autologous  (the patient's own stem cells are used),   syngeneic  (stem cells from an  identical twin ), or  allogeneic  (stem cells from a donor). [ 4 ] [ 5 ]


It is most often performed for patients with certain  cancers  of the  blood  or bone marrow, such as  multiple myeloma ,  leukemia , some types of  lymphoma  and  immune deficiencies . [ 5 ]  In these cases, the recipient's immune system is usually suppressed with  radiation  or  chemotherapy  before the transplantation. Infection and  graft-versus-host disease  are major complications of allogeneic HSCT. [ 5 ]


HSCT remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to  autoimmune diseases [ 7 ] [ 8 ]  and hereditary  skeletal dysplasias , notably  malignant infantile osteopetrosis [ 9 ] [ 10 ]  and  mucopolysaccharidosis . [ 11 ]


Indications for stem-cell transplantation are:


Many recipients of HSCTs are  multiple myeloma [ 15 ]  or  leukemia  patients [ 16 ]  who would not benefit from prolonged treatment with, or are already resistant to,  chemotherapy . Candidates for HSCTs include  pediatric  cases where the patient has an inborn defect such as  severe combined immunodeficiency  or  congenital neutropenia  with defective stem cells, and also children or adults with  aplastic anemia [ 17 ]  who have lost their stem cells after birth. Other conditions [ 18 ]  treated with stem cell transplants include  sickle cell disease ,  myelodysplastic syndrome ,  neuroblastoma ,  lymphoma ,  Ewing's sarcoma ,  desmoplastic small round cell tumor ,  chronic granulomatous disease ,  Hodgkin's disease  and  Wiskott–Aldrich syndrome . Non-myeloablative, so-called  mini transplant (microtransplantation)  procedures, have been developed requiring smaller doses of preparative chemotherapy and  radiation therapy , allowing HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen. [ 19 ]


In 2006, 50,417 first HSCTs were recorded worldwide, according to a global survey of 1,327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation.  Of these, 28,901 (57%) were autologous and 21,516 (43%) were allogeneic (11,928 from family donors and 9,588 from unrelated donors).  The main indications for transplant were lymphoproliferative disorders (55%) and leukemias (34%), and many took place in either Europe (48%) or the Americas (36%). [ 20 ]


The Worldwide Network for Blood and Marrow Transplantation reported the millionth transplant to have been undertaken in December 2012. [ 21 ]


In 2014, according to the  World Marrow Donor Association , stem-cell products provided for unrelated transplantation worldwide had increased to 20,604 (4,149 bone-marrow donations, 12,506 peripheral blood stem-cell donations, and 3,949 cord-blood units). [ 22 ]


Autologous HSCT requires the extraction ( apheresis ) of hematopoietic stem cells (HSCs) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose  chemotherapy  with or without  radiotherapy  with the intention of eradicating the patient's malignant cell population at the cost of partial or complete  bone marrow  ablation (destruction of patient's bone marrow's ability to grow new blood cells).  The patient's own stored stem cells are then transfused into his/her bloodstream, where they replace destroyed tissue and resume the patient's normal blood-cell production. [ 2 ]  Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment, since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection is very rare (and graft-versus-host disease impossible) due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as  lymphoma . [ 23 ]


For other cancers such as  acute myeloid leukemia , though, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, so the allogeneic treatment may be preferred for those conditions. [ 24 ]


Researchers have conducted small studies using nonmyeloablative HSCT as a possible treatment for  type I (insulin dependent) diabetes  in children and adults. Results have been promising, but as of 2019 [update] , speculating whether these experiments will lead to effective treatments for diabetes is premature. [ 25 ] [ 26 ] [ 27 ]  Autologous HSCT is an effective treatment against aggressive Multiple Sclerosis. [ 28 ]  The type of autologous HSCT used as a Multiple Sclerosis treatment is considered safe and the serious adverse events rare. [ 29 ]


Allogeneic HSCT involves two people – the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue ( human leukocyte antigen , HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more  loci  of the HLA gene, and a perfect match at these loci is preferred. Even if a good match exists at these critical  alleles , the recipient will require  immunosuppressive  medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA-matched sibling), syngeneic (a  monozygotic  or identical twin of the patient – necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA-matched stem cells), unrelated (donor who is not related and found to have very close degree of HLA matching), or, as in the case of Haploidentical Transplantation, a half-matched relative such as a parent, child, or sibling. Unrelated donors may be found through a registry of bone-marrow donors, such as the  National Marrow Donor Program  (NMDP) in the U.S.  A " savior sibling " may be intentionally selected by  preimplantation genetic diagnosis  to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical  cord blood  as the source of stem cells. In general, by transfusing healthy stem cells to the recipient's bloodstream to reform a healthy immune system, allogeneic HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved. [ 30 ] [ 31 ] [ 32 ]


A compatible donor is found by doing additional HLA testing from the blood of potential donors. The HLA genes fall in two categories (types I and II). In general, mismatches of the type-I genes (i.e.  HLA-A ,  HLA-B , or  HLA-C ) increase the risk of graft rejection.  A mismatch of an HLA type II gene (i.e.  HLA-DR  or   HLA-DQB1 ) increases the risk of graft-versus-host disease.  In addition, a genetic mismatch as small as a single  DNA   base pair  is significant, so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient.  Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical. [ citation needed ]


Race  and  ethnicity  are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA. [ 33 ]


As of 2013 [update] , at least two commercialized allogeneic cell therapies have been developed,  Prochymal  and  Cartistem . [ 34 ]   Omidubicel  was approved for medical use in the United States in April 2023. [ 35 ]


To limit the risks of transplanted stem-cell  rejection  or of severe graft-versus-host disease in allogeneic HSCT, the donor should preferably have the same HLA-typing as the recipient. About 25 to 30% of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease. With recent advances in  T-cell -depleting therapies such as post-transplant  cyclophosphamide ,  haploidentical  (half-matched) transplants have permitted successful transplantation of many patients who would otherwise have lacked a donor. [ 36 ]


In the case of a bone-marrow transplant, the HSCs are removed from a large bone of the donor, typically the  pelvis , through a large  needle  that reaches the center of the bone. The technique is referred to as a bone-marrow harvest and is performed under  local  or  general anesthesia . [ 37 ]


Peripheral blood stem cells [ 38 ]  are now the most common source of stem cells for HSCT. They are collected from the blood through a process known as  apheresis . The donor's blood is withdrawn through a sterile needle in one arm and passed through a machine that removes  white blood cells . The  red blood cells  are returned to the donor. The peripheral stem cell yield is boosted with daily  subcutaneous injections  of  granulocyte-colony stimulating factor , serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation. [ 39 ]


Extracting stem cells from  amniotic fluid  is possible and may have applications for  autologous  and  heterologous  use. [ 40 ]


Unlike other organs, bone-marrow cells can be frozen ( cryopreserved ) for prolonged periods without damaging too many cells. This is a necessity with autologous HSCs because the cells must be harvested from the recipient months in advance of the transplant treatment. In the case of  allogeneic transplants , fresh HSCs are preferred to avoid cell loss that might occur during the freezing and thawing process. Allogeneic cord blood is stored frozen at a  cord blood bank  because it is only obtainable at the time of  childbirth . To cryopreserve HSCs, a preservative,  dimethyl sulfoxide , must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent  osmotic  cellular injury during ice-crystal formation. HSCs may be stored for years in a cryofreezer, which typically uses  liquid nitrogen . [ 41 ]


The chemotherapy or irradiation given immediately prior to a transplant is called the conditioning regimen, the purpose of which is to help eradicate the patient's disease prior to the infusion of HSCs and to suppress immune reactions. The bone marrow can be ablated (destroyed) with dose-levels that cause minimal injury to other tissues. In allogeneic transplants, a combination of  cyclophosphamide  with  total body irradiation  is conventionally employed. This treatment also has an  immunosuppressive  effect that prevents rejection of the HSCs by the recipient's  immune system . The post-transplant prognosis often includes acute and chronic graft-versus-host disease that may be life-threatening. In certain leukemias, though, this can coincide with protection against cancer relapse owing to the  graft-versus-tumor effect . [ 42 ]  Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.


A newer treatment approach, nonmyeloablative allogeneic transplantation, also termed reduced-intensity conditioning (RIC), uses doses of chemotherapy and radiation too low to eradicate all the bone-marrow cells of the recipient. [ 43 ] : 320–321   Instead, nonmyeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor effect to resist the inherent increased risk of cancer relapse. [ 44 ] [ 45 ]  Also significantly, while requiring high doses of  immunosuppressive agents  in the early stages of treatment, these doses are less than for conventional transplants. [ 46 ]  This leads to a state of mixed  chimerism  early after transplant where both recipient and donor HSC coexist in the bone marrow space. [ 47 ]


Decreasing doses of immunosuppressive therapy then allow donor  T-cells  to eradicate the remaining recipient HSCs and to induce the graft-versus-tumor effect. This effect is often accompanied by mild graft-versus-host disease, the appearance of which is often a surrogate marker for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents. [ 48 ]


Because of their gentler conditioning regimens, these transplants are associated with a lower risk of transplant-related mortality, so allow patients who are considered too high-risk for conventional allogeneic HSCT to undergo potentially curative therapy for their disease. The optimal conditioning strategy for each disease and recipient has not been fully established, but RIC can be used in elderly patients unfit for myeloablative regimens, for whom a higher risk of cancer relapse may be acceptable. [ 43 ] [ 45 ]


After several weeks of growth in the bone marrow, expansion of HSCs and their progeny is sufficient to normalize the blood cell counts and reinitiate the immune system. The offspring of donor-derived HSCs have been documented to populate many different organs of the recipient, including the  heart ,  liver , and  muscle , and these cells had been suggested to have the abilities of regenerating injured tissue in these organs.  However, recent research has shown that such lineage infidelity does not occur as a normal phenomenon. [ 49 ]


Chimerism  monitoring is a method to monitor the balance between the patient's own stem cells and the new stem cells from a donor. In cases where the patient's own stem cells are increasing in number after treatment, the treatment may potentially not have worked as intended. [ 50 ]


HSCT is associated with a high treatment-related  mortality  in the recipient, which limits its use to conditions that are themselves life-threatening. (The one-year survival rate has been estimated to be roughly 60%, although this figure includes deaths from the underlying disease, as well as from the transplant procedure.) [ 51 ]  Major complications include  veno-occlusive disease ,  mucositis , infections ( sepsis ), graft-versus-host disease, and the development of new  malignancies . [ 52 ]


Bone-marrow transplantation usually requires that the recipient's own bone marrow be destroyed (myeloablation). Prior to the administration of new cells (engraftment), patients may go for several weeks without appreciable numbers of white blood cells to help fight  infection . This puts a patient at high risk of infections, sepsis, and  septic shock , despite  prophylactic   antibiotics . However,  antiviral   medications , such as  acyclovir  and  valacyclovir , are quite effective in prevention of HSCT-related outbreak of  herpetic  infection in  seropositive  patients. [ 53 ]  The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of  opportunistic infection . Immunosuppressive drugs are given for a minimum of six months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as  measles  or  polio . So, transplant patients must be retreated with childhood  vaccines  once they are off immunosuppressive medications. [ 54 ]


Severe liver injury can result from hepatic veno-occlusive disease (VOD), newly termed sinusoidal obstruction syndrome (SOS). [ 55 ]  Elevated levels of  bilirubin ,  hepatomegaly , and fluid retention are clinical hallmarks of this condition. The appreciation of the generalized cellular injury and obstruction in  hepatic vein  sinuses is now greater. Severe cases of SOS are associated with a high mortality rate.  Anticoagulants  or  defibrotide  may be effective in reducing the severity of VOD but may also increase bleeding complications.  Ursodiol  has been shown to help prevent VOD, presumably by facilitating the flow of  bile .


The injury of the mucosal lining of the mouth and throat is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening, but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition. [ 56 ]


The mucosal lining of the bladder is affected in about 5% of children undergoing HSCT. This causes  hematuria  (blood in urine), frequent urination, abdominal pain and  thrombocytopenia . [ 57 ]


Graft-versus-host disease (GvHD) is an inflammatory disease that is unique to allogeneic transplantation. It is an attack by the "new" bone marrow's immune cells against the recipient's tissues. This can occur even if the donor and recipient are HLA-identical because the immune system can still recognize other differences between their tissues. It is named graft-versus-host disease because the transplanted cells must accept the body rather than the body accepting the new cells. [ 58 ]


Acute GvHD typically occurs in the first three months after transplantation and may involve the  skin ,  intestine , or  liver . High-dose  corticosteroids , such as  prednisone , are a standard treatment, but this immunosuppressive treatment often leads to deadly infections. Chronic GvHD may also develop after allogeneic transplant. It is the major source of late treatment-related complications, although it less often results in death. In addition to inflammation, chronic GvHD may lead to the development of  fibrosis , or scar tissue, similar to  scleroderma ; it may cause functional disability and require prolonged immunosuppressive therapy. GvHD is usually mediated by T cells, which react to foreign peptides presented on the  major histocompatibility complex  of the host. [ 59 ]


Further research is needed to determine whether mesenchymal stromal cells can be use for prophylaxis and treatment of GvHD. [ 60 ]


Graft-versus-tumor effect (GVT), or "graft versus leukemia" effect, is the beneficial aspect of the GvHD phenomenon. For example, HSCT patients with either acute, or in particular chronic, GvHD after an allogeneic transplant tend to have a lower risk of cancer relapse. [ 61 ] [ 42 ]  This is due to a therapeutic immune reaction of the grafted donor T lymphocytes against the diseased bone marrow of the recipient. This lower rate of relapse accounts for the increased success rate of allogeneic transplants, compared to transplants from identical twins, and indicates that allogeneic HSCT is a form of immunotherapy. GVT is the major benefit of transplants that do not employ the highest immunosuppressive regimens.


Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and in some cases multiple myeloma, but is less effective in rapidly growing acute leukemias. [ 62 ]


If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells ( donor lymphocyte infusion ). [ 62 ]


Patients after HSCT are at a higher risk for  oral   carcinoma . Post-HSCT  oral cancer  may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients. [ 63 ]


A meta-analysis showed that the risk of secondary cancers such as  bone cancer ,  head and neck cancers , and  melanoma , with standardized incidence ratios of 10.04 (3.48–16.61), 6.35 (4.76–7.93), and 3.52 (2.65–4.39), respectively, was significantly increased after HSCT. So, diagnostic tests for these cancers should be included in the screening program of these patients for the prevention and early detection of these cancers. [ 64 ]


Prognosis  in HSCT varies widely dependent upon disease type, stage, stem-cell source, HLA-matched status (for allogeneic HSCT), and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immunosuppressive treatments and the spectrum of opportunistic infections can be survived. [ 30 ] [ 31 ]  In recent years, survival rates have been gradually improving across almost all populations and subpopulations receiving transplants. [ 65 ]


Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror  et al ., [ 66 ]  using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the  Fred Hutchinson Cancer Research Center  in the U.S. The HCT-CI modifies and adds to a well-validated comorbidity index, the  Charlson Comorbidity Index  (CCI) (Charlson,  et al .) [ 67 ]  The CCI was previously applied to patients undergoing allogeneic HCT, but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.


Patients who were successfully treated with HSCT and total body irradiation in childhood were found to have increased fat mass percentage, leading to significantly decreased exercise capacity in adulthood. This suggests patients who underwent successful treatment with HSCT have an increased predisposition to cardiovascular disease later in life. [ 68 ]


The risks of a complication depend on patient characteristics, health care providers, and the apheresis procedure, and the colony-stimulating factor used ( G-CSF ). G-CSF drugs include  filgrastim  (Neupogen, Neulasta), and  lenograstim  (Graslopin).


Filgrastim is typically dosed in the 10 microgram/kg level for 4–5 days during the harvesting of stem cells. The documented adverse effects of filgrastim include  splenic rupture ,  acute respiratory distress syndrome , alveolar hemorrhage, and allergic reactions (usually experienced in first 30 minutes). [ 69 ] [ 70 ] [ 71 ]  In addition, platelet and hemoglobin levels dip postprocedurally, not returning to normal until after a month. [ 71 ]


The question of whether geriatrics (patients over 65) react the same as patients under 65 has not been sufficiently examined.  Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to induce genetic changes in  agranulocytes  of normal donors. [ 70 ]  There is no statistically significant evidence either for or against the hypothesis that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by G-CSF in susceptible individuals. [ 72 ]


Blood is drawn from a peripheral vein in a majority of patients, but a central line to the jugular, subclavian, and femoral veins may be used. Adverse reactions during apheresis were experienced in 20% of women and 8% of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea. [ 71 ]


A study involving 2,408 donors (aged 18–60 years) indicated that  bone pain  (primarily back and hips) as a result of filgrastim treatment is observed in 80% of donors. [ 71 ]  Donation is not recommended for those with a history of back pain. [ 71 ]  Other symptoms observed in more than 40 percent of donors include muscle pain, headache, fatigue, and difficulty sleeping. [ 71 ]  These symptoms all returned to baseline 1 month after donation in the majority of patients. [ 71 ]


In one meta-study that incorporated data from 377 donors, 44% of patients reported having adverse side effects after peripheral blood HSCT. [ 72 ]  Side effects included pain prior to the collection procedure as a result of G-CSF injections, and postprocedural generalized skeletal pain, fatigue, and reduced energy. [ 72 ]


A study that surveyed 2,408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6%), although none of these events was fatal. [ 71 ]  Donors were not observed to have higher than normal rates of cancer with up to 4–8 years of follow-up. [ 71 ]
One study based on a survey of medical teams covered about 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about one in 1,500. [ 70 ]  This study reported a cardiovascular-related fatality risk within the first 30 days of HSCT of about two in 10,000. [ 70 ]


In 1939, a woman with aplastic anaemia received the first human bone marrow transfusion. This patient received regular blood transfusions, and an attempt was made to increase her leukocyte and platelet counts by intravenous bone marrow injection without unexpected reaction. [ 73 ]


Stem-cell transplantation was pioneered using bone marrow-derived stem cells by a team at the  Fred Hutchinson Cancer Research Center  from the 1950s through the 1970s led by  E. Donnall Thomas , whose work was later recognized with a  Nobel Prize in Physiology or Medicine . Thomas' work showed that bone-marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening graft-versus-host disease. [ 74 ]  Collaborating with  Eloise Giblett , a professor at the  University of Washington , he discovered genetic markers that could confirm donor matches.


The first physician to perform a successful human bone-marrow transplant on a disease other than cancer was  Robert A. Good  at the  University of Minnesota  in 1968. [ 75 ]
In 1975, John Kersey, also of the University of Minnesota, performed the first successful bone-marrow transplant to cure lymphoma. His patient, a 16-year-old-boy, is today the longest-living lymphoma transplant survivor. [ 76 ]


At the end of 2012, 20.2 million people had registered their willingness to be a bone-marrow donor with one of the 67 registries from 49 countries participating in  Bone Marrow Donors Worldwide . Around 17.9 million of these registered donors had been ABDR typed, allowing easy matching.  A further 561,000 cord blood units had been received by one of 46 cord blood banks from 30 countries participating.  The highest total number of bone-marrow donors registered were those from the U.S. (8.0 million), and the highest number per capita were those from Cyprus (15.4% of the population). [ 77 ]


Within the U.S., racial minority groups are the least likely to be registered, so are the least likely to find a potentially life-saving match.  In 1990, only six African Americans were able to find a bone-marrow match, and all six had common European genetic signatures. [ 78 ]


Africans are more genetically diverse than people of European descent, which means that more registrations are needed to find a match. Bone marrow and cord blood banks exist in  South Africa , and a new program is beginning in  Nigeria . [ 78 ]  Many people belonging to different races are requested to donate as a shortage of donors exists in African, mixed race, Latino, aboriginal, and many other communities.


Two registries in the U.S. recruit unrelated allogeneic donors: NMDP or Be the Match, and the  Gift of Life Marrow Registry .


In 2007, a team of doctors in Berlin, Germany, including  Gero Hütter , performed a stem-cell transplant for  leukemia  patient  Timothy Ray Brown , who was also  HIV -positive. [ 79 ]  From 60 matching donors, they selected a  [CCR5]-Δ32 homozygous  individual with two  genetic copies  of a rare variant of a  cell surface receptor . This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1,000 people of European ancestry have this inherited  mutation , but it is rarer in other populations. [ 80 ] [ 81 ]  The transplant was repeated a year later after a leukemia relapse. Over three years after the initial transplant, and despite discontinuing  antiretroviral therapy , researchers cannot detect HIV in the transplant recipient's blood or in various biopsies of his tissues. [ 82 ]  Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV, but scientists emphasise that this is an unusual case. [ 83 ]  Potentially fatal transplant complications (the "Berlin patient" developed graft-versus-host disease and  leukoencephalopathy ) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found. [ 84 ] [ 85 ]


In 2012,  Daniel Kuritzkes  reported results of two stem-cell transplants in patients with HIV.  They did not, however, use donors with the Δ32 deletion. After their transplant procedures, both were put on antiretroviral therapies, during which neither showed traces of HIV in their blood plasma and purified  CD4 +  T cells  using a sensitive culture method (less than 3 copies/ml). The virus was once again detected in both patients some time after the discontinuation of therapy. [ 86 ]


In 2019, a British man became the second to be cleared of HIV after receiving a bone-marrow transplant from a virus-resistant (Δ32) donor. This patient is being called "the London patient" (a reference to the famous Berlin patient). [ 87 ]


Since McAllister's 1997 report on a patient with  multiple sclerosis  (MS) who received a bone-marrow transplant for chronic myelogenous leukemia (CML), [ 88 ]  over 600 reports have been published describing HSCTs performed primarily for MS. [ 89 ]  These have been shown to "reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients" who have aggressive, highly active MS, "in the absence of chronic treatment with disease-modifying agents". [ 89 ]  A randomized clinical trial including 110 patients showed that HSCT significantly prolonged time to disease progression compared to disease-modifying therapy. [ 90 ]  Long-term outcome in patients with severe disease has showed that complete disease remission after HSCT is possible. [ 91 ]


HSCT can also be used for treating selected, severe cases of other autoimmune neurological diseases such as  neuromyelitis optica ,  chronic inflammatory demyelinating polyneuropathy , and  myasthenia gravis . [ 92 ]


Peripheral blood stem cell transplantation  ( PBSCT ), also called "Peripheral stem cell support", [ 1 ]  is a method of replacing  blood-forming   stem cells . Stem cells can be destroyed through cancer treatments such as chemotherapy or radiation, as well as any blood-related diseases, such as  leukemia ,  lymphoma ,  neuroblastoma  and  multiple myeloma . [ 2 ]  PBSCT is now a much more common procedure than its  bone marrow harvest  equivalent due to the ease and less invasive nature of the procedure. [ 3 ] [ 4 ]  Studies suggest that PBSCT has a better outcome in terms of the number of  hematopoietic stem cell  ( CD34+ cells ) yield. [ 5 ]


Immature  hematopoietic stem cells  in the circulating  blood  that are similar to those in the  bone marrow  are collected by  apheresis  from a donor (PBSC collection). The product is then administered  intravenously  to the patient after treatment. The administered  hematopoietic stem cells  then migrate to the recipient's bone marrow, through a process known as  stem cell homing , where the transplanted cells override the previous  bone marrow . This allows the  bone marrow  to recover, proliferate and continue producing healthy  blood cells . [ citation needed ]


The transplantation may be  autologous  (an individual's own blood cells),  allogeneic  (blood cells donated by someone else with matching  HLA ), or  syngeneic  (blood cells donated by an  identical twin ). The apheresis procedure typically lasts for 4–6 hours, depending on the  blood volume  of the donor. [ 6 ]


Granulocyte colony stimulating factor  (GCSF) are naturally occurring  glycoproteins  that stimulate white blood cell proliferation.  Filgrastim  is a synthetic form of GCSF produced in  E.coli . [ 7 ]  PBSC donors are given a course of GCSF prior to PBSC collection. The increase in white blood cell proliferation as a result of the Filgrastim ensures a better results from the donation. The course is usually given over a 4-day period prior to PBSC collection. [ 8 ]  The most common side effects of Filgrastim are bone, joint, back, arm, leg, mouth, throat, and muscle pain. [ 9 ]  Additionally, headache, nausea, vomiting, dizziness, fatigue, rash, loss of appetite, and difficulty falling or staying asleep are common. [ 9 ]


Since  allogeneic  PBSCT involves transformation of blood between different individuals, this naturally carries more complications than  autologous  PBSCT. [ 10 ]
For example, calculations must be made to ensure consistency in the amount of total blood volume between the donor and recipient. If the total blood volume of the donor is less than that of the recipient (such as when a child is donating to an adult), multiple PBSCT sessions may be required for adequate collection. Performing such a collection in a single setting could result in risks such as  hypovolemia , which could lead to  cardiac arrest  and death. Health care providers must exercise careful precaution when considering donor-recipient matching in  allogeneic  PBSCT. [ 11 ]


An early example of a successful peripheral stem cell transplant was carried out in the wake of the  1999 Tokaimura nuclear accident . Hisashi Ouchi, who received the highest dose of  radiation  was treated with PBSCT in an attempt to restore his destroyed immune system. Cells from the patient's sister's bone marrow were administered, and in the following weeks successfully began dividing and differentiating into  white blood cells . However, several weeks later, the cells were found to have been mutated by the radiation still present within the patient's body, and were observed carrying out  autoimmune responses . [ 12 ]  Later studies on the incident and subsequent use of PBSCT found that the transplant had also induced  neoendothelialization  of the aortic  endothelium . [ 13 ]


This article incorporates  public domain material  from  Dictionary of Cancer Terms .  U.S. National Cancer Institute .


Hematoporphyrin  ( Photodyn ,  Sensibion ) is a  porphyrin  prepared from  hemin .  It is a derivative of  protoporphyrin IX , where the two vinyl groups have been hydrated (converted to alcohols). It is a deeply colored solid that is usually encountered as a solution.  Its  chemical structure  was determined in 1900. [ 1 ]


It is used as a photosensitizer in  photodynamic therapy .  Acetylation of hematoporphyrin followed by hydrolysis of the product of that reaction affords a mixture called  hematoporphyrin derivative  (HPD), which is also used in photodynamic therapy. [ 2 ]


Hematoporphyrin has also been used as an  antidepressant  and  antipsychotic  since the 1920s. [ 3 ] [ 4 ]


This  drug  article relating to the  nervous system  is a  stub . You can help Wikipedia by  expanding it .


A  hemoglobinometer  or  haemoglobinometer  ( British English ) is a medical device used to measure  hemoglobin   concentration  in  blood . [ 4 ]  It can operate by  spectrophotometric measurement  of hemoglobin concentration. Portable hemoglobinometers provide easy and convenient measurement of hematological variables, especially in areas where  clinic laboratories  are unavailable. [ 5 ]


As per guidelines of  National AIDS Control Organisation  (NACO) for accurate results & mass screening, [ citation needed ]  analysis using hemoglobinometer is a recommended method used for  absorbance  measurement of whole blood at Hb/HbO2/ Isobestic point , [ citation needed ]  based on  microcuvette  technology such as HemoCue 301 [ 6 ]  and Mokshit-Chanda-AM005A. [ 7 ]


Hemolysis  or  haemolysis  ( / h iː ˈ m ɒ l ɪ s ɪ s / ), [ 1 ]  also known by  several other names , is the rupturing ( lysis ) of  red blood cells  (erythrocytes) and the release of their contents ( cytoplasm ) into surrounding fluid (e.g.  blood plasma ). Hemolysis may occur  in vivo  or  in vitro .


One cause of hemolysis is the action of  hemolysins , toxins that are produced by certain  pathogenic bacteria  or  fungi . Another cause is intense physical exercise. [ 2 ]   Hemolysins  damage the red blood cell's  cytoplasmic membrane , causing lysis and eventually cell death. [ 3 ]


From hemo- + -lysis, from  Ancient Greek   αἷμα  ( haîma , 'blood') +  λύσις   lúsis , 'loosening').


Hemolysis inside the body can be caused by a large number of medical conditions, including some parasites ( e.g. ,  Plasmodium ), some autoimmune disorders ( e.g. , autoimmune haemolytic anaemia, drug-induced  hemolytic anemia ,  atypical hemolytic uremic syndrome  (aHUS) [ 4 ] ), [ 5 ]  some genetic disorders ( e.g. ,  Sickle-cell disease  or  G6PD deficiency ), or blood with too low a solute concentration ( hypotonic  to cells). [ 6 ]


Hemolysis can lead to  hemoglobinemia  due to  hemoglobin  released into the  blood plasma , which plays a significant role in the  pathogenesis  of  sepsis [ 7 ]  and can lead to increased risk of infection due to its inhibitory effects on the  innate immune system . [ 7 ]


Because the feeding process of the  Plasmodium  parasites damages red blood cells,  malaria  is sometimes called "parasitic hemolysis" in medical literature. [ citation needed ]


Hemolytic disease of the newborn is an autoimmune disease resulting from the mother's antibodies crossing the placenta to the fetus. This most often occurs when the mother has previously been exposed to blood antigens present on the fetus but foreign to her, through either a blood transfusion or a previous pregnancy. [ 8 ]


Because  in vivo  hemolysis destroys red blood cells, in uncontrolled, chronic or severe cases it can lead to  hemolytic anemia .