A hemolytic crisis, or hyperhemolytic crisis, is characterized by an accelerated rate of red blood cell destruction leading to  anemia ,  jaundice , and  reticulocytosis . [ 9 ]  Hemolytic crises are a major concern with  sickle-cell disease  and  G6PD deficiency .


Paxillus involutus  ingestion can cause hemolysis.


Spaceflight can cause hemolysis. [ 10 ]


Hemolysis may result from intrinsic defects in the red blood cell itself: [ 11 ] [ 12 ]


Extrinsic hemolysis is caused by the red blood cell's environment: [ 5 ] [ 6 ]


Intravascular hemolysis  describes hemolysis that happens mainly inside the  vasculature . [ 16 ]  As a result, the contents of the red blood cell are released into the general circulation, leading to  hemoglobinemia [ 17 ]  and increasing the risk of ensuing  hyperbilirubinemia . [ 18 ]


Intravascular hemolysis may occur when red blood cells are targeted by  autoantibodies , leading to  complement  fixation, or by damage by parasites such as  Babesia . [ 19 ]  Additionally, thrombotic microangiopathy (TMA) can result in hemolysis of red blood cells. [ 20 ]  TMA is frequently observed in  aHUS  patients where clots form in the small vessels of the kidney resulting in damaged red blood cells as they attempt to pass through the restricted vessels. [ 21 ]


Extravascular hemolysis  refers to hemolysis taking place in the  liver ,  spleen ,  bone marrow , and  lymph nodes . [ 16 ]  In this case little hemoglobin escapes into  blood plasma . [ 18 ]  The  macrophages  of the  reticuloendothelial system  in these organs  engulf and destroy  structurally-defective red blood cells, or those with antibodies attached, and release unconjugated bilirubin into the blood plasma circulation. [ 22 ] [ 23 ]  Typically, the spleen destroys mildly abnormal red blood cells or those coated with  IgG-type antibodies , [ 24 ] [ 25 ]  while severely abnormal red blood cells or those coated with  IgM-type antibodies  are destroyed in the circulation or in the liver. [ 24 ]


If extravascular hemolysis is extensive,  hemosiderin  can be deposited in the spleen, bone marrow, kidney, liver, and other organs, resulting in  hemosiderosis . [ 18 ]


In vitro  hemolysis can be caused by improper technique during collection of blood specimens, by the effects of mechanical processing of blood, or by bacterial action in cultured blood specimens.


Most causes of  in vitro  hemolysis are related to specimen collection. Difficult collections, unsecure line connections, contamination, and incorrect needle size, as well as improper tube mixing and incorrectly filled tubes are all frequent causes of hemolysis. [ 27 ]  Excessive suction can cause the red blood cells to be smashed on their way through the  hypodermic needle  owing to turbulence and physical forces. Such hemolysis is more likely to occur when a patient's veins are difficult to find or when they collapse when blood is removed by a syringe or a modern vacuum tube. Experience and proper technique are key for any  phlebotomist , nurse or doctor to prevent hemolysis.


In vitro  hemolysis during specimen collection can cause inaccurate laboratory test results by contaminating the surrounding plasma with the contents of hemolyzed red blood cells. For example, the concentration of  potassium  inside red blood cells is much higher than in the plasma and so an elevated potassium level is usually found in biochemistry tests of hemolyzed blood.


After the blood collection process,  in vitro  hemolysis can still occur in a sample due to external factors, such as prolonged storage, incorrect storage conditions and excessive physical forces by dropping or vigorously mixing the tube.


In some surgical procedures (especially some heart operations) where substantial blood loss is expected, machinery is used for  intraoperative blood salvage . A centrifuge process takes blood from the patient, washes the red blood cells with  normal saline , and returns them to the patient's blood circulation. Hemolysis may occur if the centrifuge rotates too quickly (generally greater than 500 rpm)—essentially this is hemolysis occurring outside of the body. Increased hemolysis occurs with massive amounts of sudden blood loss, because the process of returning a patient's cells must be done at a correspondingly higher speed to prevent  hypotension ,  pH  imbalance, and a number of other hemodynamic and blood level factors.  Modeling of fluid flows to predict the likelihood of red cell membrane rupture in response to stress is an active area of research. [ 28 ]


Visualizing the physical appearance of hemolysis in cultured blood samples may be used as a tool to determine the species of various  Gram-positive bacteria  infections ( e.g. ,  Streptococcus ).


Hemolysis is sometimes called  hematolysis ,  erythrolysis , or  erythrocytolysis . The words  hemolysis  ( / h iː ˈ m ɒ l ɪ s ɪ s / ) [ 1 ]  and  hematolysis  ( / ˌ h iː m ə ˈ t ɒ l ɪ s ɪ s / ) [ 29 ]  both use  combining forms  conveying the idea of " lysis  of blood" ( hemo-  or  hemato-  +  -lysis ). The words  erythrolysis  ( / ˌ ɛr ə ˈ θ r ɒ l ɪ s ɪ s / ) [ 30 ]  and  erythrocytolysis  ( / ə ˌ r ɪ θ r oʊ s aɪ ˈ t ɒ l ɪ s ɪ s / ) [ 31 ]  both use combining forms conveying the idea of " lysis  of erythrocytes" ( erythro-  ±  cyto-  +  -lysis ).


Red blood cells (erythrocytes) have a short lifespan (approximately 120 days), and old ( senescent ) cells are constantly removed and replaced with new ones via  erythropoiesis . This breakdown/replacement process is called erythrocyte turnover. In this sense, erythrolysis or hemolysis is a normal process that happens continually. However, these terms are usually used to indicate that the lysis is  pathological .


Pulmonary hypertension has been gaining recognition as a complication of chronic hereditary and acquired hemolysis. [ 32 ] [ 33 ] [ 34 ]  Free hemoglobin released during hemolysis inactivates the  vasodilator  nitric oxide (NO). [ 32 ]  Hemolysis also releases  arginase  that depletes  L-arginine , the substrate needed for NO synthesis. [ 32 ] [ 34 ]  This reduces NO-dependent vasodilation [ 32 ]  and induces  platelet  activation,  thrombin  generation,  procoagulant  factors and  tissue factor  activation, [ 32 ]  contributing to the formation of  thrombosis . [ 32 ]  This can lead to  esophageal spasm  and  dysphagia ,  abdominal pain ,  erectile dysfunction ,  systemic hypertension ,  decreased organ perfusion , promotion of  inflammation  and  coagulation , and  thrombosis . [ 35 ]


Chronic hemolysis may also lead to  endothelial dysfunction , heightened  endothelin -1-mediated responses and  vasculopathy . [ 32 ] [ 36 ]   The release of  heme  leads to the production of  bilirubin  and depletion of plasma proteins, such as  albumin ,  haptoglobin , and  hemopexin , which may lead to  jaundice . [ 37 ] [ 38 ]  It may also lead to increased levels of the heme breakdown product  stercobilin  in the stool. [ 24 ]


Splenectomy  of those with hemolytic disorders appears to increase risk of developing  pulmonary thrombosis . [ 32 ]


Complications may also arise from the increased workload for the kidney as it secretes  erythropoietin  to stimulate the  bone marrow  to produce more  reticulocytes  (red blood cell precursors) to compensate for the loss of red blood cells due to hemolysis. [ 24 ]


Hemorheology ,  also spelled   haemorheology  ( haemo  from  Greek  ‘αἷμα,  haima  ' blood '; and  rheology , from Greek ῥέω  rhéō , ' flow ' and -λoγία,  -logia  'study of'), or  blood rheology , is the study of flow properties of blood and its elements of  plasma  and  cells . Proper tissue  perfusion  can occur only when blood's  rheological  properties are within certain levels. Alterations of these properties play significant roles in disease processes. [ 1 ]  Blood  viscosity  is determined by plasma viscosity,  hematocrit  (volume fraction of red blood cell, which constitute 99.9% of the cellular elements) and mechanical properties of  red blood cells . Red blood cells have unique mechanical behavior, which can be discussed under the terms  erythrocyte deformability  and  erythrocyte aggregation . [ 2 ]  Because of that, blood behaves as a  non-Newtonian fluid . As such, the viscosity of blood varies with  shear rate . Blood becomes less viscous at high shear rates like those experienced with increased flow such as during exercise or in peak- systole . Therefore, blood is a  shear-thinning  fluid. Contrarily, blood viscosity increases when shear rate goes down with increased vessel diameters or with low flow, such as downstream from an obstruction or in  diastole .  Blood viscosity also increases with increases in red cell aggregability.


Blood viscosity is a measure of the resistance of blood to flow. It can also be described as the thickness and stickiness of blood. This  biophysical  property makes it a critical determinant of friction against the  vessel  walls, the rate of  venous return , the work required for the  heart  to pump blood, and how much  oxygen  is transported to tissues and organs. These functions of the  cardiovascular system  are directly related to  vascular resistance ,  preload ,  afterload , and  perfusion , respectively. [ citation needed ]


The primary determinants of blood viscosity are  hematocrit ,  red blood cell deformability ,  red blood cell aggregation , and  plasma  viscosity. Plasma's viscosity is determined by water-content and  macromolecular  components, so these factors that affect blood viscosity are the  plasma protein  concentration and types of  proteins  in the plasma. [ 3 ]  Nevertheless, hematocrit has the strongest impact on whole blood viscosity. One unit increase in hematocrit can cause up to a 4% increase in blood viscosity. [ 2 ]  This relationship becomes increasingly sensitive as hematocrit increases. When the hematocrit rises to 60 or 70%, which it often does in  polycythemia , [ 4 ]  the blood viscosity can become as great as 10 times that of water, and its flow through blood vessels is greatly retarded because of increased resistance to flow. [ 5 ]  This will lead to decreased  oxygen delivery . [ 6 ]  Other factors influencing blood viscosity include  temperature , where an increase in temperature results in a decrease in viscosity. This is particularly important in  hypothermia , where an increase in blood viscosity will cause problems with blood circulation.


Many conventional cardiovascular risk factors have been independently linked to whole blood viscosity.


Anemia  can reduce blood viscosity, which may lead to  heart failure . [ 7 ]
Furthermore, elevation of plasma viscosity correlates to the progression of  coronary  and  peripheral artery diseases . [ 3 ] [ 4 ]


In  pascal - seconds  (Pa·s), the  viscosity

 μ

 {\displaystyle \mu }

  of blood at 37 °C is normally 3 × 10 −3  to 4 × 10 −3 , [ 8 ]  respectively 3 - 4 centi poise  (cP) in the  centimetre gram second system of units .


μ
 =
 (
 3
 ∼
 4
 )
 ⋅

 10

 −
 3

 P
 a
 ⋅
 s

 {\displaystyle \mu =(3\sim 4)\cdot 10^{-3}\,Pa\cdot s}


ν
 =

 μ
 ρ

 =

 (
 3
 ∼
 4
 )
 ⋅

 10

 −
 3

 P
 a
 ⋅
 s

 1.06
 ⋅

 10

 3

 k
 g

 m

 3

 =
 (
 2.8
 ∼
 3.8
 )
 ⋅

 10

 −
 6

 m

 2

 s

 {\displaystyle \nu ={\frac {\mu }{\rho }}={\frac {(3\sim 4)\cdot 10^{-3}Pa\cdot s}{1.06\cdot 10^{3}{\frac {kg}{m^{3}}}}}=(2.8\sim 3.8)\cdot 10^{-6}\,{\frac {m^{2}}{s}}}

 ,


where

 ρ

 {\displaystyle \rho }

  is the density. Blood viscosity can be measured by viscometers capable of measurements at various shear rates, such as a rotational  viscometer . [ 9 ]


Blood is a  viscoelastic  fluid, meaning that it possesses both viscous and fluid characteristics. The viscous component arises primarily through the  viscosity  of blood plasma, while the  elastic  component arises from deformation of the  red blood cells . As the heart contracts,  mechanical energy  is transferred from the heart to the blood; a small part of the energy is dissipated by the viscosity of the  suspension , another part is stored as elastic energy in the red blood cells, and the remaining energy is used to drive blood circulation and is thus converted to  kinetic energy . Viscoelastic fluids make up a larger class of fluids called  non-Newtonian fluids .


The red blood cells occupy about half of the volume of blood and possess elastic properties.  This elastic property is the largest contributing factor to the viscoelastic behavior of blood. The large volume percentage of red blood cells at a normal  hematocrit  level leaves little room for cell motion and deformation without interacting with a neighboring cell.  Calculations have shown that the maximum volume percentage of red blood cells without deformation is 58% which is in the range of normally occurring levels. [ 10 ]  Due to the limited space between red blood cells, it is obvious that in order for blood to flow, significant cell to cell interaction will play a key role.  This interaction and tendency for cells to aggregate is a major contributor to the viscoelastic behavior of blood. Red blood cell deformation and aggregation is also coupled with flow-induced changes in the arrangement and orientation as a third major factor in its viscoelastic behavior. [ 11 ] [ 12 ]  Other factors contributing to the viscoelastic properties of blood is the plasma viscosity, plasma composition, temperature, and the rate of flow or shear rate. Together, these factors make human blood  viscoelastic , non- Newtonian , and  thixotropic . [ 13 ]


When the red cells are at rest or at very small shear rates, they tend to aggregate and stack together in an energetically favorable manner. The attraction is attributed to charged groups on the surface of cells and to the presence of fibrinogen and globulins. [ 14 ]  This aggregated configuration is an arrangement of cells with the least amount of deformation. With very low shear rates, the viscoelastic property of blood is dominated by the aggregation and cell deformability is relatively insignificant. As the shear rate increases the size of the aggregates begins to decrease. With a further increase in shear rate, the cells will rearrange and orient to provide channels for the plasma to pass through and for the cells to slide. In this low to medium shear rate range, the cells wiggle with respect to the neighboring cells allowing flow. The influence of aggregation properties on the viscoelasticity diminish and the influence of red cell deformability begins to increase.  As shear rates become large, red blood cells will stretch or deform and align with the flow. Cell layers are formed, separated by plasma, and flow is now attributed to layers of cells sliding on layers of plasma. The cell layer allows for easier flow of blood and as such there is a reduced viscosity and reduced elasticity. The viscoelasticity of the blood is dominated by the deformability of the red blood cells.


Maxwell Model concerns Maxwell fluids or  Maxwell material . The material in Maxwell Model is a  fluid  which means it respects continuity properties for conservative equations :  Fluids are a subset of the phases of matter and include liquids, gases, plasmas and, to some extent, plastic solids. Maxwell model is made to estimate local conservative values of viscoelasticity by a global measure in the integral volume of the model to be transposed to different flow situations. Blood is a complex material where different cells like red blood cells are discontinuous in plasma. Their size and shape are irregular too because they are not perfect spheres. Complicating moreover blood volume shape, red cells are not identically distributed in a blood sample volume because they migrate with velocity gradients in direction to the highest speed areas calling the famous representation of the  Fåhræus–Lindqvist effect , aggregate or separate in sheath or plug flows described by Thurston. [ 15 ]  Typically, the Maxwell Model described below is uniformly considering the material (uniform blue color) as a perfect distributed particles fluid everywhere in the volume (in blue) but Thurston reveals that packs of red cells, plugs, are more present in the high speed region, if  y  is the height direction in the Maxwell model figure, ( y ~H) and there is a free cells layer in the lower speed area ( y ~0) what means the plasma fluid phase that deforms under Maxwell Model is strained following inner linings that completely escape from the analytical model by Maxwell. [ citation needed ]


In theory, a fluid in a Maxwell Model behaves exactly similarly in any other flow geometry like pipes, rotating cells or in rest state. But in practice, blood properties vary with the geometry and blood has shown being an inadequate material to be studied as a fluid in common sense. So Maxwell Model gives trends that have to be completed in real situation followed by Thurston model  [ 15 ]  in a vessel regarding distribution of cells in sheath and plug flows. [ citation needed ]


If a small cubical volume of blood is considered, with forces being acted upon it by the heart pumping and shear forces from boundaries.  The change in shape of the cube will have 2 components:


When the force is removed, the cube would recover partially.  The elastic deformation is reversed but the slippage is not.  This explains why the elastic portion is only noticeable in unsteady flow.  In steady flow, the slippage will continue to increase and the measurements of non time varying force will neglect the contributions of the elasticity.


Figure 1 can be used to calculate the following parameters necessary for the evaluation of blood when a force is exerted.


A sinusoidal time varying flow is used to simulate the pulsation of a heart. A viscoelastic material subjected to a time varying flow will result in a phase variation between

 τ

 {\displaystyle \tau }

  and

 γ

 {\displaystyle \gamma }

  represented by

 ϕ

 {\displaystyle \phi }

 . If

 ϕ
 =
 0

 {\displaystyle \phi =0}

 , the material is a purely elastic because the stress and strain are in phase, so that the response of one caused by the other is immediate. If

 ϕ

 {\displaystyle \phi }

  = 90°, the material is a purely viscous because strain lags behind stress by 90 degrees. A viscoelastic material will be somewhere in between 0 and 90 degrees.


The sinusoidal time variation is proportional to

 e

 i
 ω
 t

 {\displaystyle e^{i\omega t}}

 . Therefore, the size and phase relation between the stress, strain, and shear rate are described using this relationship and a radian frequency,

 ω
 =
 2
 π
 f

 {\displaystyle \omega =2\pi f}

  were

 f

 {\displaystyle f}

  is the frequency in  Hertz .


The components of the complex shear stress can be written as:


Where

 τ
 ′

 {\displaystyle \tau '}

  is the viscous stress and

 τ
 ″

 {\displaystyle \tau ''}

  is the elastic stress.
The complex coefficient of viscosity

 η

 ∗

 {\displaystyle \eta ^{*}}

  can be found by taking the ratio of the complex shear stress and the complex shear rate: [ 16 ]


Similarly, the complex dynamic modulus G can be obtained by taking the ratio of the complex  shear stress  to the complex shear strain.


Relating the equations to common viscoelastic terms we get the storage modulus, G', and the loss modulus, G".


A viscoelastic  Maxwell material  model is commonly used to represent the viscoelastic properties of  blood .  It uses purely viscous damper and a purely elastic spring connected in series. Analysis of this model gives the complex viscosity in terms of the dashpot constant and the spring constant.


One of the most frequently used constitutive models for the  viscoelasticity  of blood is the Oldroyd-B model. There are several variations of the Oldroyd-B non-Newtonian model characterizing shear thinning behavior due to red blood cell aggregation and dispersion at low shear rate. Here we consider a three-dimensional Oldroyd-B model coupled with the momentum equation and the total stress tensor. [ 17 ]   A non Newtonian flow is used which insures that the viscosity of blood

 μ
 (
 h
 ,
 d
 )

 {\displaystyle \mu (h,d)}

  is a function of vessel diameter d and hematocrit h. In the Oldroyd-B model, the relation between the shear stress tensor B and the orientation stress tensor A is given by:


S
 +
 γ

 [

 D
 S

 D
 t

 −
 Δ
 V
 ⋅
 S
 −
 S
 ⋅

 (
 Δ
 V
 )

 T

 ]

 =
 μ
 (
 h
 ,
 d
 )

 [

 B
 +
 γ

 (

 D
 B

 D
 t

 −
 Δ
 V
 ⋅
 B
 −
 B
 ⋅

 (
 Δ
 V
 )

 T

 )

 ]

 −
 g
 A
 +

 C

 1

 (

 g
 A
 −

 C

 2

 I

 μ
 (
 h
 ,
 d

 )

 2

 )

 {\displaystyle S+\gamma \left[{\frac {DS}{Dt}}-\Delta V\cdot S-S\cdot {(\Delta V)}^{T}\right]=\mu (h,d)\left[B+\gamma \left({\frac {DB}{Dt}}-\Delta V\cdot B-B\cdot {(\Delta V)}^{T}\right)\right]-gA+C_{1}\left(gA-{\frac {C_{2}I}{\mu (h,d)^{2}}}\right)}


where D/Dt is the material derivative, V is the velocity of the fluid, C1, C2, g,

 γ

 {\displaystyle \gamma }

  are constants. S and B are defined as follows:


Red blood cells are subjected to intense mechanical stimulation from both blood flow and vessel walls, and their rheological properties are important to their effectiveness in performing their biological functions in the microcirculation. [ 18 ]  Red blood cells by themselves have been shown to exhibit viscoelastic properties. There are several methods used to explore the mechanical properties of red blood cells such as:


These methods worked  to characterize the deformability of the red blood cell in terms of the shear, bending, area expansion moduli, and relaxation times. [ 20 ]  However, they were not able to explore the viscoelastic properties. Other techniques have been implemented such as photoacoustic measurements. This technique uses a single-pulse laser beam to generate a photoacoustic signal in tissues and the decay time for the signal is measured. According to the theory of linear viscoelasticity, the decay time is equal to the viscosity-elasticity ratio and therefore the viscoelasticity characteristics of the red blood cells could be obtained. [ 21 ]


Another experimental technique used to evaluate viscoelasticity consisted of using Ferromagnetism beads bonded to a cells surface. Forces are then applied to the magnetic bead using optical magnetic twisting cytometry which allowed researchers to explore the time dependent responses of red blood cells. [ 22 ]


T

 s

 (
 t
 )

 {\displaystyle T_{s}(t)}

  is the mechanical torque per unit bead volume (units of stress) and is given by:


where H is the applied magnetic twisting field,

 θ

 {\displaystyle {\theta }}

  is the angle of the bead’s magnetic moment relative to the original magnetization direction, and c is the bead constant which is found by experiments conducted by placing the bead in a fluid of known viscosity and applying a twisting field.


Complex  Dynamic modulus  G can be used to represent the relations between the oscillating stress and strain:


where

 G
 ′

 {\displaystyle G'}

  is the  storage modulus  and

 G
 ″

 {\displaystyle G''}

  is the  loss modulus :


where

 σ

 0

 {\displaystyle \sigma _{0}}

  and

 ε

 0

 {\displaystyle \varepsilon _{0}}

  are the amplitudes of stress and strain and

 ϕ

 {\displaystyle \phi }

  is the phase shift between them.


From the above relations, the components of the complex modulus are determined from a loop that is created by comparing the change in torque with the change in time which forms a loop when represented graphically.  The limits of

 T

 s

 (
 t
 )

 {\displaystyle T_{s}(t)}

  - d(t) loop and the area, A, bounded by the

 T

 s

 (
 t
 )

 {\displaystyle T_{s}(t)}

  - d(t) loop, which represents the energy dissipation per cycle, are used in the calculations. The phase angle

 ϕ

 {\displaystyle \phi }

 , storage modulus G', and loss modulus G  then become:


where d is the displacement.


The hysteresis shown in figure 3 represents the viscoelasticity present in red blood cells.  It is unclear if this is related to membrane molecular fluctuations or metabolic activity controlled by intracellular concentrations of  ATP . Further research is needed to fully explore these interaction and to shed light on the underlying viscoelastic deformation characteristics of the red blood cells.


When looking at viscoelastic behavior of blood  in vivo , it is necessary to also consider the effects of  arteries ,  capillaries , and  veins . The viscosity of blood has a primary influence on flow in the larger arteries, while the elasticity, which resides in the elastic deformability of red blood cells, has primary influence in the arterioles and the capillaries. [ 23 ]  Understanding wave propagation in arterial walls, local hemodynamics, and wall shear stress gradient is important in understanding the mechanisms of cardiovascular function. Arterial walls are anisotropic and heterogeneous, composed of layers with different bio-mechanical characteristics which makes understanding the mechanical influences that arteries contribute to blood flow very difficult. [ 24 ]


From a medical standpoint, the importance of studying the viscoelastic properties of blood becomes evident. With the development of cardiovascular prosthetic devices such as heart valves and blood pumps, the understanding of pulsating blood flow in complex geometries is required. A few specific examples are the effects of viscoelasticity of blood and its implications for the testing of a pulsatile Blood Pumps. [ 25 ]  Strong correlations between blood viscoelasticity and regional and global cerebral blood flow during cardiopulmonary bypass have been documented. [ 26 ]


This has also led the way for developing a blood analog in order to study and test prosthetic devices.  The classic analog of glycerin and water provides a good representation of viscosity and inertial effects but lacks the elastic properties of real blood. One such blood analog is an aqueous solution of Xanthan gum and glycerin developed to match both the viscous and elastic components of the complex viscosity of blood. [ 27 ]


Normal red blood cells are deformable but many conditions, such as  sickle cell disease , reduce their elasticity which makes them less deformable. Red blood cells with reduced deformability have increasing impedance to flow, leading to an increase in red blood cell aggregation and reduction in oxygen saturation which can lead to further complications. The presence of cells with diminished deformability, as is the case in sickle cell disease, tends to inhibit the formation of plasma layers and by measuring the viscoelasticity, the degree of inhibition can be quantified. [ 28 ]


In early theoretical work, blood was treated as a non-Newtonian viscous fluid. Initial studies had evaluated blood during steady flow and later, using oscillating flow. [ 29 ]  Professor George B. Thurston, of the University of Texas, first presented the idea of blood being viscoelastic in 1972.  The previous studies that looked at blood in steady flow showed negligible elastic properties because the elastic regime is stored in the blood during flow initiation and so its presence is hidden when a flow reaches steady state.  The early studies used the properties found in steady flow to derive properties for unsteady flow situations. [ 30 ] [ 31 ]   Advancements in medical procedures and devices required a better understanding of the mechanical properties of blood. [ citation needed ]


The relationships between shear stress and shear rate for blood must be determined experimentally and expressed by  constitutive equations .  Given the complex macro-rheological behavior of blood, it is not surprising that a single equation fails to completely describe the effects of various rheological variables (e.g.,  hematocrit , shear rate).  Thus, several approaches to defining these equations exist, with some the result of curve-fitting experimental data and others based on a particular rheological model.


The finding that, for blood flowing steadily in tubes with diameters of less than 300 micrometres, the average hematocrit of the blood in the tube is less than the hematocrit of the blood in the reservoir feeding the tube is known as the Fåhræus effect.  This effect is generated in the concentration entrance length of the tube, in which erythrocytes move towards the central region of the tube as they flow downstream.  This entrance length is estimated to be about the distance that the blood travels in a quarter of a second for blood where red blood cell aggregation is negligible and the vessel diameter is greater than about 20 micrometres. [ 1 ]


As the characteristic dimension of a flow channel approaches the size of the particles in a suspension; one should expect that the simple continuum model of the suspension will fail to be applicable.  Often, this limit of the applicability of the continuum model begins to manifest itself at characteristic channel dimensions that are about 30 times the particle diameter: in the case of blood with a characteristic RBC dimension of 8 μm, an apparent failure occurs at about 300 micrometres.  This was demonstrated by Fåhraeus and Lindqvist, who found that the apparent viscosity of blood was a function of tube diameter for diameters of 300 micrometres and less when they flowed constant-hematocrit blood from a well-stirred reservoir through a tube. The finding that for small tubes with diameters below about 300 micrometres and for faster flow rates which do not allow appreciable erythrocyte aggregation, the effective viscosity of the blood depends on tube diameter is known as the Fåhræus–Lindqvist effect. [ 1 ]


Hemosiderin  or  haemosiderin  is an  iron -storage complex that is composed of partially digested ferritin and  lysosomes . The breakdown of  heme  gives rise to  biliverdin  and iron. [ 1 ] [ 2 ]  The body then traps the released iron and stores it as hemosiderin in tissues. [ 3 ]  Hemosiderin is also generated from the abnormal metabolic pathway of  ferritin . [ 3 ]


It is only found within cells (as opposed to circulating in blood) and appears to be a complex of  ferritin , denatured ferritin and other material. [ 4 ] [ 5 ]  The iron within deposits of hemosiderin is very poorly available to supply iron when needed.  Hemosiderin can be identified histologically with  Perls' Prussian blue  stain ; iron in hemosiderin turns blue to black when exposed to potassium ferrocyanide. [ 6 ]  In normal animals, hemosiderin deposits are small and commonly inapparent without special stains. Excessive accumulation of hemosiderin is usually detected within cells of the  mononuclear phagocyte system  (MPS) or occasionally within  epithelial cells  of the liver and kidney.


Several disease processes result in deposition of larger amounts of hemosiderin in tissues; although these deposits often cause no symptoms, they can lead to  organ damage .


Hemosiderin is most commonly found in  macrophages  and is especially abundant in situations following  hemorrhage , suggesting that its formation may be related to  phagocytosis  of  red blood cells  and  hemoglobin . Hemosiderin can accumulate in different  organs  in various  diseases .


Iron is required by many of the  chemical reactions  (i.e., oxidation-reduction reactions) in the body but is  toxic  when not properly contained. Thus, many methods of iron storage have developed.


Hemosiderin often forms after bleeding (haemorrhage). [ 7 ]  When blood leaves a ruptured blood vessel, the  red blood cell  dies, and the hemoglobin of the cell is released into the extracellular space. Phagocytic cells (of the  mononuclear phagocyte system ) called macrophages engulf (phagocytose) the hemoglobin to degrade it, producing hemosiderin and  biliverdin . Excessive systemic accumulations of hemosiderin may occur in macrophages in the liver, lungs, spleen, kidneys, lymph nodes, and bone marrow. These accumulations may be caused by excessive red blood cell destruction (haemolysis), excessive iron uptake/hyperferraemia, or decreased iron utilization (e.g., anaemia of copper toxicity) uptake hypoferraemia (which often leads to iron deficiency anemia).


Cellular iron is found as either ferritin or hemosiderin. It is identified in cells by the Perls or Prussian blue reaction, in which ionic iron reacts with acid ferrocyanide to impart a blue color.<Wintrobe's Clinical Hematology>


Hemosiderin may deposit in diseases associated with iron overload. [ 8 ]  These diseases are typically diseases in which chronic blood loss requires frequent  blood transfusions , such as  sickle cell anemia  and  thalassemia .


In  biology ,  hemostasis   or   haemostasis  is a process to prevent and stop  bleeding , meaning to keep  blood  within a damaged  blood vessel  (the opposite of hemostasis is  hemorrhage ). It is the first stage of  wound healing .  Hemostasis involves three major steps:


Coagulation, the changing of blood from a liquid to a  gel  which forms the fibrin clots, is essential to hemostasis. Intact blood vessels moderate blood's tendency to form  clots . The  endothelial  cells of intact vessels prevent blood clotting with a heparin-like molecule and  thrombomodulin , and prevent platelet aggregation with  nitric oxide  and  prostacyclin . When endothelium of a blood vessel is damaged, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete  von Willebrand factor , which initiates the maintenance of hemostasis after injury. These processes seal the injury or hole until tissues are healed.


The word  hemostasis  ( / ˌ h iː m oʊ ˈ s t eɪ s ɪ s / , [ 1 ] [ 2 ]   sometimes   / ˌ h iː ˈ m ɒ s t ə s ɪ s / ) uses the  combining forms   hemo-  and  -stasis ,  Neo-Latin  from  Ancient Greek   αἱμο-   haimo-  (similar to  αἷμα   haîma ), meaning "blood", and  στάσις   stásis , meaning " stasis ", yielding "motionlessness or stopping of blood".


Hemostasis occurs when blood is present outside of the body or blood vessels. It is the innate response for the body to stop bleeding and loss of blood. During hemostasis three steps occur in a rapid sequence. Vascular spasm is the first response as the blood vessels constrict to allow less blood to be lost. In the second step, platelet plug formation,  platelets  stick together to form a temporary seal to cover the break in the vessel wall. The third and last step is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a "molecular glue". [ 3 ]  Platelets are a large factor in the hemostatic process. They allow for the creation of the "platelet plug" that forms almost directly after a blood vessel has been ruptured. Within seconds of a blood vessel's epithelial wall being disrupted, platelets begin to adhere to the sub- endothelium  surface. It takes approximately sixty seconds until the first fibrin strands begin to intersperse among the wound. After several minutes the platelet plug is completely formed by fibrin. [ 4 ]  Hemostasis is maintained in the body via three mechanisms:


Hemostasis can be achieved in various other ways if the body cannot do it naturally (or needs help) during surgery or medical treatment. When the body is under shock and stress, hemostasis is harder to achieve. Though natural hemostasis is most desired, having other means of achieving this is vital for survival in many emergency settings. Without the ability to stimulate hemostasis the risk of  hemorrhaging   is great. During surgical procedures, the types of hemostasis listed below can be used to control bleeding while avoiding and reducing the risk of tissue destruction. Hemostasis can be achieved by  chemical agent  as well as mechanical or physical agents. Which hemostasis type used is determined based on the situation. [ 8 ]


Developmental Haemostasis  refers to the differences in the haemostatic system between children and adults.


Debates by physicians and medical practitioners still continue to arise on the subject of hemostasis and how to handle situations with large injuries. If an individual acquires a large injury resulting in extreme blood loss, then a  hemostatic agent  alone would not be very effective. Medical professionals continue to debate on what the best ways are to assist a patient in a chronic state; however, it is universally accepted that hemostatic agents are the primary tool for smaller bleeding injuries. [ 8 ]


Some main types of hemostasis used in emergency medicine include:


The body's hemostasis system requires careful regulation in order to work properly. If the blood does not clot sufficiently, it may be due to bleeding disorders such as  hemophilia  or  immune thrombocytopenia ; this requires careful investigation. Over-active clotting can also cause problems;  thrombosis , where blood clots form abnormally, can potentially cause  embolisms , where blood clots break off and subsequently become lodged in a vein or artery. [ citation needed ]


Hemostasis disorders can develop for many different reasons. They may be  congenital , due to a deficiency or defect in an individual's platelets or clotting factors. A number of disorders can be acquired as well, such as in  HELLP syndrome , which is due to pregnancy, or  Hemolytic-uremic syndrome  (HUS), which is due to  E. coli  toxins.


The process of preventing blood loss from a vessel or organ of the body is referred to as hemostasis. The term comes from the  Ancient Greek  roots "heme" meaning blood, and "stasis" meaning halting; Put together means the "halting of the blood". [ 3 ]
The origin of hemostasis dates back as far as ancient Greece; first referenced to being used in the  Battle of Troy . It started with the realization that excessive bleeding inevitably equaled death. Vegetable and mineral styptics were used on large wounds by the Greeks and Romans until the takeover of Egypt around 332BC by Greece. At this time many more advances in the general medical field were developed through the study of Egyptian  mummification  practice, which led to greater knowledge of the hemostatic process. It was during this time that many of the veins and arteries running throughout the human body were found and the directions in which they traveled. Doctors of this time realized if these were plugged, blood could not continue to flow out of the body. Nevertheless, it took until the invention of the printing press during the fifteenth century for medical notes and ideas to travel westward, allowing for the idea and practice of hemostasis to be expanded. [ 13 ]


There is currently a great deal of research being conducted on hemostasis. The most current research is based on genetic factors of hemostasis and how it can be altered to reduce the cause of  genetic disorders  that alter the natural process hemostasis. [ 14 ]


Von Willebrand disease  is associated with a defect in the ability of the body to create the platelet plug and the fibrin mesh that ultimately stops the bleeding. New research is concluding that the von Willebrand disease is much more common in adolescence. This disease negatively hinders the natural process of Hemostasis causing excessive bleeding to be a concern in patients with this disease. There are complex treatments that can be done including a combination of therapies,  estrogen - progesterone  preparations,  desmopressin , and Von Willebrand factor concentrates. Current research is trying to find better ways to deal with this disease; however, much more research is needed in order to find out the effectiveness of the current treatments and if there are more operative ways to treat this disease. [ 15 ]


Haemotoxins ,  hemotoxins  or  hematotoxins  are  toxins   that destroy  red blood cells , disrupt  blood   clotting , and/or cause  organ  degeneration and generalized  tissue  damage. The term  haemotoxin  is to some degree a  misnomer  since toxins that damage the blood also damage other tissues. Injury from a haemotoxic agent is often very painful and can cause permanent damage and in severe cases death. Loss of an affected limb is possible even with prompt treatment.


Haemotoxins are frequently employed by  venomous  animals, including snakes ( vipers  and  pit vipers ) and spiders ( brown recluse ). Animal venoms contain  enzymes  and other  proteins  that are haemotoxic or  neurotoxic  or occasionally both (as in the  Mojave rattlesnake , the  Japanese mamushi , [ 1 ]  and similar species). In addition to killing the prey, part of the function of a haemotoxic venom for some animals is to aid digestion. The venom breaks down protein in the region of the bite, making prey easier to digest.


The process by which a haemotoxin causes death is much slower than that of a  neurotoxin .  Snakes which envenomate a prey animal may have to track the prey as it flees.  Typically, a  mammalian  prey will stop fleeing not because of death, but due to shock caused by the venomous bite. Symptoms are dependent upon species, size, location of bite and the amount of venom injected. In humans, symptoms include nausea, disorientation, and headache; these may be delayed for several hours.


Haemotoxins are used in  diagnostic  studies of the  coagulation  system.  Lupus anticoagulant  is detected by changes in the  dilute Russell's viper venom time , which is a  laboratory  assay based on—as its name indicates—venom of the  Russell's viper .


Histolysis  is the decay and dissolution of organic tissues or of blood. It is sometimes referred to as  histodialysis . [ 1 ]  In cells, histolysis may be caused by  uracil-DNA  degradation. [ 2 ]


Origin: New Latin, from  Greek   ‘ιστος  (histos) tissue +  λυσις  (lusis) dissolution from  λυειν  to loosen, dissolve.


Histolysis is associated with  metamorphosis  as well as other morphological changes. The loss of organs or blood begins with  cell death , which can be caused by a number of factors. In frogs, the histolysis of the tail associated with metamorphosis is also associated with a lowering of the  pH  of the blood. [ 3 ]
Increases in histolysis has been found to correspond with the pupal phase of insect metamorphosis, wherein larval organs break down before the  histogenesis  of the adult tissues occur. The histolysis is associated with an increase in the production of  ATP  and a decrease in metabolism.  [ 4 ]


Thomas Hodgkin   RMS  (17 August 1798 – 5 April 1866) was a British  physician , considered one of the most prominent  pathologists  of his time and a pioneer in  preventive medicine . He is now best known for the first account of  Hodgkin's disease , a form of  lymphoma  and  blood disease , in 1832. [ 1 ]  Hodgkin's work marked the beginning of times when a pathologist was actively involved in the clinical process. He was a contemporary of  Thomas Addison   and  Richard Bright  at  Guy's Hospital  in London.


Thomas Hodgkin was born to a  Quaker  family in  Pentonville ,  St. James Parish, Middlesex , the son of  John Hodgkin . [ 2 ]  He received private education with his brother  John Hodgkin , and in 1816 took a position as private secretary to  William Allen . [ 3 ]  His aim was to learn the trade of  apothecary , one of the routes into medicine, and Allen, despite prominence in that business, did not make it possible. They parted, and Hodgkin went to an apothecary cousin, John Glaisyer, in  Brighton  instead. [ 4 ]  He inherited property from his great-uncle of the same name, meaning that from age 21 he had a degree of financial independence. [ 5 ]


In September 1819 Hodgkin was admitted to  St. Thomas' and Guy's Medical School . He "walked the wards" for a year on the rounds of physicians and surgeons, and attended lectures, in particular those by  Astley Cooper . [ 6 ]  He then studied at the  University of Edinburgh , where the lecturers who impressed him included  Andrew Duncan, the younger , and  Robert Jameson  in natural history. His first published paper, on the  spleen , came from Duncan's course, and drew on the veterinary writings of his friend  Bracy Clark . [ 7 ]  During his time as a student, he became a member of the  Royal Medical Society . [ citation needed ]


In 1821, Hodgkin went to France, where he learned to work with the  stethoscope , a recent invention of  René Laennec . He also took account of the exacting statistical and clinical approach of  Pierre Charles Alexandre Louis . [ 8 ]  He associated there with British expatriates including  Robert Knox  and  Helen Maria Williams . [ 9 ]  In 1823, he qualified for his M.D. at the  University of Edinburgh Medical School  with a thesis on the physiological mechanisms of absorption in animals. [ 10 ]


In Paris Hodgkin met  Benjamin Thorpe , a banker for Rothschild's at the time, who was suffering from  tuberculosis . Hodgkin became his physician for a while, and Thorpe was cured. [ 11 ]  This contact led to another appointment as physician to Abraham Montefiore, married to Henriette, daughter of  Mayer Amschel Rothschild . Once graduated at Edinburgh, Hodgkin joined the couple for travel in Italy. Abraham was seriously ill with tuberculosis (he died in 1824) and the position proved unsatisfactory for both sides, with Hodgkin dismissed. But the relationship he built up with  Moses Montefiore , Abraham's brother, proved a lifelong friendship. [ 12 ]


Staying in Paris for an extended period from September 1824 to June 1825, Hodgkin made significant medical contacts. The Edwards brothers,  William-Frédéric Edwards  and  Henri Milne Edwards , were both physiologists with distinctive theories, and Hodgkin looked over their work in the next few years.  Achille-Louis Foville  was a neurologist, around whom Hodgkin tried unsuccessfully, from 1838, to set up a southern version of the  York Retreat . [ 13 ] [ 14 ]


Hodgkin found a position at Guy's, first as a volunteer clerk in 1825, and then in 1826 as the curator of the museum there, also carrying out autopsies. He built up his reputation on the work his posts brought him in morbid anatomy ( anatomical pathology  as it is now called). [ 15 ]


Hodgkin's hospital career came to an end, however, in 1837, when he clashed with the autocratic  Benjamin Harrison . Harrison disliked Hodgkin's progressive views, and support for the new  University College, London , and had been personally offended by them in one instance (see below). [ 3 ]  There were two confrontational interviews in which Harrison went over pretexts for not giving Hodgkin a promotion (to Assistant Physician); Hodgkin had also been ill not long before. His friends pushed the issue to an acrimonious vote of the governors, which was in fact hopeless. The position went to the rival candidate  Benjamin Guy Babington , and Hodgkin moved reluctantly into private practice, after a period of convalescence. [ 16 ]  In 1840 he attended the  World Anti-Slavery Convention  in London representing the  Aborigines Protection Society . [ 17 ]


Hodgkin had a further period of involvement with hospital medicine, when in 1842 he was asked to take charge of teaching at  St. Thomas' Hospital . After joint management of Guy's and St. Thomas' had ended in 1825, St. Thomas' had found itself eclipsed as a medical school by its former partner. Hodgkin was brought in, and found new lecturers in  Marshall Hall  and  George Gregory ; he lectured himself, and with Charles Barker the four embarked on a lecture series. He also drew on his experience at Guy's to improve the museum and start a Clinical Society for reporting of cases. The outcome, however, was unsatisfactory for him. Hall was much preferred as lecturer, and Gregory, lecturing on  skin diseases , gained a reputation for clarity, and wrote a textbook. But Hodgkin was not asked to continue lecturing for another year, ending the relationship. [ 18 ] [ 19 ]


In around 1847, Hodgkin became guardian to an Aboriginal Australian youth,  Warrulan , who had been brought to England in 1845 by  Edward John Eyre , [ 20 ]  arranging for him to be educated at the Quaker  Sibford School . [ 21 ]


Hodgkin married in 1850 Sarah Frances Scaife, a widow; they had no children. [ 2 ]  When Lady Montefiore died in 1862, Hodgkin promised her to travel with her husband on future journeys. [ 22 ]  He accompanied  Moses Montefiore  to Palestine in 1866. There he contracted  dysentery  and died on 4 April 1866. He was buried in  Jaffa .


Hodgkin like many other Quakers was concerned both with the  abolition of slavery  and the reduction of the impact of western colonization on indigenous peoples around the world. He stood aside from the  Anti-Slavery Society  of the 1820s and 1830s, however; the society took a different line on emancipation and colonization in Africa. It refused in the early 1830s to publish his views. [ 23 ]  Hodgkin began to take multiple initiatives of his own.


Hodgkin had an interest in both the  physical anthropology  and the cultural aspects of what would now be  ethnology , before the academic disciplines existed. In his role as keeper of the Museum at Guy's, he collected specimens from peoples from around the world. [ 24 ]  In 1827, in a letter supporting the missionary  Hannah Kilham  who was working with West African languages, he published for the first time long-held ideas on " civilisation "; [ 25 ]  a Civilization Society in London had been a Hodgkin family initiative some years earlier. [ 26 ]  In helping to found the  Aborigines Protection Society , he argued that languages constituted philological evidence of man's origins, and should therefore be preserved where threatened; [ 27 ]  he had written a paper on the topic, and proposed a questionnaire, for the  Philological Society  in 1835. [ 28 ]


For Hodgkin, language was a  racial trait . [ 29 ]  In Paris around the end of 1838, he prevailed upon W. F. Edwards to form a French society with the same aims as the Aborigines Protection Society; and in 1839 the  Société Ethnologique de Paris  was set up in accordance with Edwards's own ideas. [ 30 ]  This development was reflected in 1843 when the  Ethnological Society of London  was set up, diverging from the Aborigines Protection Society by its scientific and linguistic interests, and disconnecting from missionary work. [ 31 ]


Hodgkin was a supporter of  Liberia  in the early days of its foundation; and he compared it favourably to  Sierra Leone . [ 32 ]  In supporting  Elliott Cresson  and the  American Colonization Society , he put himself outside the mainstream of Quaker and abolitionist thinking. When the American  abolitionist ,  William Lloyd Garrison , toured in England in 1833, Hodgkin tried at first to mediate between Garrison and Cresson. The formation, however, of the  British African Colonization Society  by Cresson had Hodgkin's support, and he found himself isolated from natural allies who were Quakers or physicians. There were personal attacks on Hodgkin from the Garrison camp. [ 33 ]


Hodgkin became involved in campaigning concerning the  Boothia Peninsula  and the  Hudson's Bay Company  around 1836–37, through his friend  Richard King . King had been on the expedition of Captain  George Back  in the north of Canada of 1833–35, and had written an 1836 book, his  Narrative , on it; he advocated a further expedition in the same area in 1836–37, a cause Hodgkin took up. Sensitive commercial interests were involved, as the Hudson's Bay Company's license was due for renewal in 1841. [ 34 ]  The  Narrative  contained a piece Hodgkin had written on the indifference of the company to the indigenous peoples of western Canada. [ 35 ]  Hodgkin then took up the behaviour of the company with Benjamin Harrison, Treasurer of Guy's, disastrously mixing his professional life with his activism: Harrison was concerned in the management of the company as deputy chairman, and was related by marriage to  John Henry Pelly , the chairman, who had crossed swords with King at parliamentary hearings. [ 36 ]


Hodgkin's concerns over the indigenous peoples in the Hudson's Bay Company territory in western Canada continued. They were pursued both by correspondence with  Sir George Simpson , and in the pages of the  Intelligencer  of the Aborigines Protection Society. [ 37 ]


Hodgkin collaborated with  Joseph Jackson Lister , who in 1830 enunciated design principles for the  achromatic  microscope. [ 38 ]  By that time Hodgkin and Lister had already published research on tissue samples, based on observations made with Lister's innovative microscope, in particular on the "globule hypothesis" of the time which was held in particular by Henri Milne Edwards. [ 39 ]  They denied the existence of globules in tissue;  Ernst Heinrich Weber  in 1830 contradicted them, and the debate continued for a decade. [ 40 ]  For a while microscopy suffered in its reputation, but by 1840  histology  was a recognised discipline, and in time the view of Hodgkin and Lister that "globules" were optical artefacts became accepted. [ 41 ]  The 1827 paper they published has been called "the foundation of modern histology". [ 42 ]


Hodgkin described the disease that bears his name ( Hodgkin lymphoma ) in 1832, in a paper titled  On Some Morbid Appearances of the Absorbent Glands and Spleen . [ 43 ]  He received 33 years later the  eponym  through the recognition of British physician  Samuel Wilks , who rediscovered the disease. It is a malignancy that produces enlargement of  lymphoid tissue ,  spleen , and  liver , with invasion of other tissues. A more benign form is called  Hodgkin's paragranuloma , while a more invasive form is called  Hodgkin's sarcoma . [ citation needed ]


Hodgkin published as a book his  Lectures on Morbid Anatomy  in 1836 and 1840. His major contribution to the teaching of pathology, however, was made in 1829, with his two volumed work entitled  The Morbid Anatomy of Serous and Mucous Membranes , which became a classic in modern pathology. [ citation needed ]


Hodgkin was one of the earliest defenders of preventive medicine, having published  On the Means of Promoting and Preserving Health  in book form in 1841. Among other early observations were the first description of acute  appendicitis , of the biconcave format of  red blood cells  and the striation of  muscle  fibers.


Hodgkin also translated with Thomas Fisher, from the French of William-Frédéric Edwards,  On the Influence of Physical Agents on Life  (London, 1832; Philadelphia 1838). [ 44 ] [ 45 ]  Edwards was a  vitalist  in physiology, who studied the effect of physical forces on processes in living organisms. [ 46 ]  The work as it appeared in English was much more than a translation, since it contained an appendix of over 200 pages containing two dozen papers, a compendium of medicine and science tangentially related to themes in Edwards, but related to his general approach. It included early work by Hodgkin and collaboration with Lister, as well as something on electricity and meteorology. [ 47 ]  He also published  The Means of Promoting and Preserving Health  (London, 1840), of which a second edition appeared in 1841, and an  Address on Medical Reform  (1847). [ 2 ]


Other works by Hodgkin were  Biographical Sketches : of  James Cowles Prichard  (1849); and of William Stroud (1789–1858), a medical collaborator. He also wrote abolitionist pamphlets and on the British African Colonization Societies (1833–1834). [ 2 ] [ 48 ]


There is a  blue plaque  on his house in  Bedford Square , London.  The Friends' School, Hobart  named one of the four school houses after him. [ citation needed ]


The  King's College London   School of Medicine's  Hodgkin Building is named in honour of Hodgkin. [ 49 ]


Homing  is the phenomenon whereby  cells  migrate to the organ of their origin. By homing, transplanted  hematopoietic  cells are able to travel to and engraft (establish residence) in the  bone marrow . Various  chemokines [ 1 ]  and  receptors [ 2 ]   are involved in the homing of  hematopoietic stem cells . [ 3 ]


The  hook effect  refers to the  prozone phenomenon , also known as  antibody excess , or the  postzone phenomenon , also known as  antigen excess .  It is an  immunologic  phenomenon whereby the effectiveness of  antibodies  to form  immune complexes  can be impaired when concentrations of an antibody or an antigen are very high. The formation of immune complexes stops increasing with greater concentrations and then decreases at extremely high concentrations, producing a  hook  shape on a  graph  of measurements. An important practical relevance of the phenomenon is as a type of interference that plagues certain  immunoassays  and  nephelometric assays , resulting in  false negatives  or inaccurately low results. Other common forms of interference include antibody interference,  cross-reactivity  and signal interference. The phenomenon is caused by very high concentrations of a particular  analyte  or  antibody  and is most prevalent in one-step (sandwich)  immunoassays . [ 2 ] [ 3 ]


In an  agglutination  test, a person's  serum  (which contains  antibodies ) is added to a  test tube , which contains a particular  antigen . If the antibodies interact with the antigen to form  immune complexes , called agglutination, then the test is interpreted as positive. However, if too many antibodies that can bind to the antigen are present, then the antigenic sites are coated by antibodies, and few or no antibodies directed toward the pathogen are able to bind more than one antigenic particle. [ 4 ]  Since the antibodies do not bridge between antigens, no agglutination occurs. Because no agglutination occurs, the test is interpreted as negative. In this case, the result is a false negative. The range of relatively high antibody concentrations within which no reaction occurs is called the  prozone . [ 5 ]


The effect can also occur because of antigen excess, when both the capture and detection antibodies become saturated by the high analyte concentration. In this case, no sandwich can be formed by the capturing antibody, the antigen and the detection antibody. In this case, free antigen is in competition with captured antigen for detection antibody binding. [ 6 ]  Sequential addition of antigen and antibody, paired with stringent washing, can prevent the effect, as can increasing the relative concentration of antibody to antigen, thereby mediating the effect. [ citation needed ]


Examples include high levels of  syphilis  antibodies in  HIV  patients or high levels of cryptococcal antigen leading to false negative tests in undiluted samples. [ 7 ] [ 8 ]  This phenomenon is also seen in serological tests for Brucellosis. [ citation needed ]  It may be seen in precipitation reactions. The antibody that fails to react is known as the  blocking antibody  and prevents the precipitating antibody from binding to the antigens. Thus the proper precipitation reaction does not take place. However, when the serum is diluted, the blocking antibody is as well and its concentration decreases enough for the proper precipitation reaction to occur. [ 9 ]


Lewis Thomas  described in his memoir a physiologic experiment of 1941 in which he observed the prozone effect  in vivo : immunity in rabbits to  meningococcus , which was robust, unexpectedly decreased when  immunization  was used to induce a heightened antibody response. [ 10 ]  In other words, getting the rabbits' bodies to produce more antibodies against this bacterium had the counterproductive effect of decreasing their immunity to it. From the viewpoint of an overly simplistic notion of the antibody/antigen relationship, this seems  paradoxical , although it is clearly logical from a viewpoint duly informed by present-day molecular biology. Thomas was interested in pursuing this physiologic research further, and remained so for decades afterward, but his career took him in other directions and he was not aware of anyone having pursued it by the time of his memoir. [ 10 ]  One kind of relevance that he hypothesized for this in vivo  blocking antibody  concept was as a driver of human susceptibility to certain infectious diseases. [ 10 ]  In the decades since, the concept has also been found to have clinical relevance in  allergen immunotherapy , where blocking antibodies can interfere with other antibodies involved in hypersensitivity and thus improve allergy treatment. [ 11 ]


Human iron metabolism  is the set of chemical reactions that maintain  human homeostasis  of  iron  at the systemic and cellular level.  Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease.  Hematologists  have been especially interested in systemic iron  metabolism , because iron is essential for  red blood cells , where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of  iron overload , such as  hereditary hemochromatosis , and  iron deficiency , such as  iron-deficiency anemia .


Iron is an essential bioelement for most forms of life, from  bacteria  to  mammals . Its importance lies in its ability to mediate electron transfer. In the ferrous state (Fe 2+ ), iron acts as an  electron donor , while in the ferric state (Fe 3+ ) it acts as an  acceptor . Thus, iron plays a vital role in the  catalysis  of enzymatic reactions that involve electron transfer (reduction and oxidation,  redox ). Proteins can contain iron as part of different  cofactors , such as  iron–sulfur clusters  (Fe-S) and  heme  groups, both of which are assembled in  mitochondria .


Human cells require iron in order to obtain energy as  ATP  from a multi-step process known as cellular respiration, more specifically from  oxidative phosphorylation  at the mitochondrial  cristae . Iron is present in the iron–sulfur cluster and heme groups of the  electron transport chain  proteins that generate a  proton gradient  that allows  ATP synthase  to synthesize ATP ( chemiosmosis ).


Heme groups are part of  hemoglobin , a protein found in red blood cells that serves to transport oxygen from the  lungs  to other tissues. Heme groups are also present in  myoglobin  to store and diffuse oxygen in muscle cells.


The human body needs iron for oxygen transport. Oxygen (O 2 ) is required for the functioning and survival of nearly all cell types. Oxygen is transported from the lungs to the rest of the body bound to the  heme  group of  hemoglobin  in red blood cells. In muscles cells, iron binds oxygen to  myoglobin , which regulates its release.


Iron is also potentially toxic. Its ability to donate and accept electrons means that it can catalyze the conversion of  hydrogen peroxide  into  free radicals . Free radicals can cause damage to a wide variety of cellular structures, and ultimately kill the cell. [ 1 ]


Iron bound to proteins or  cofactors  such as  heme  is safe. Also,  there are virtually no truly free iron ions in the cell, since they readily form complexes with organic molecules. However, some of the intracellular iron is bound to low-affinity complexes, and is termed labile iron or "free" iron. Iron in such complexes can cause damage as described above. [ 2 ]


To prevent that kind of damage, all life forms that use iron bind the iron atoms to  proteins . This binding allows cells to benefit from iron while also limiting its ability to do harm. [ 1 ] [ 3 ]  Typical intracellular labile iron concentrations in bacteria are 10-20 micromolar, [ 4 ]  though they can be 10-fold higher in anaerobic environment, [ 5 ]  where free radicals and  reactive oxygen species  are scarcer. In mammalian cells, intracellular labile iron concentrations are typically smaller than 1 micromolar, less than 5 percent of total cellular iron. [ 2 ]


In response to a systemic bacterial infection, the immune system initiates a process known as " iron withholding ". If bacteria are to survive, then they must obtain iron from their environment. Disease-causing bacteria do this in many ways, including releasing iron-binding molecules called  siderophores  and then reabsorbing them to recover iron, or scavenging iron from hemoglobin and  transferrin . The harder the bacteria have to work to get iron, the greater a  metabolic price  they must pay. That means that iron-deprived bacteria reproduce more slowly. So, control of iron levels appears to be an important defense against many bacterial infections. Certain bacteria species have developed strategies to circumvent that defense,  TB  causing bacteria can reside within  macrophages , which present an iron rich environment and  Borrelia burgdorferi  uses  manganese  in place of iron. People with increased amounts of iron, as, for example, in hemochromatosis, are more susceptible to some bacterial infections. [ 6 ]


Although this mechanism is an elegant response to short-term bacterial infection, it can cause problems when it goes on so long that the body is deprived of needed iron for red cell production. Inflammatory  cytokines  stimulate the liver to produce the iron metabolism regulator protein  hepcidin , that reduces available iron. If hepcidin levels increase because of non-bacterial sources of inflammation, like viral infection, cancer, auto-immune diseases or other chronic diseases, then the  anemia of chronic disease  may result. In this case, iron withholding actually impairs health by preventing the manufacture of enough hemoglobin-containing red blood cells. [ 3 ]


Most well-nourished people in industrialized countries have 4 to 5 grams of iron in their bodies (~38 mg iron/kg body weight for women and ~50 mg iron/kg body for men). [ 7 ]  Of this, about  2.5 g  is contained in the hemoglobin needed to carry oxygen through the blood (around 0.5 mg of iron per mL of blood), [ 8 ]  and most of the rest (approximately 2 grams in adult men, and somewhat less in women of childbearing age) is contained in  ferritin  complexes that are present in all cells, but most common in bone marrow,  liver , and  spleen . The liver stores of ferritin are the primary physiologic source of reserve iron in the body. The reserves of iron in industrialized countries tend to be lower in children and women of child-bearing age than in men and in the elderly. Women who must use their stores to compensate for iron lost through  menstruation ,  pregnancy  or  lactation  have lower non-hemoglobin body stores, which may consist of  500 mg , or even less.


Of the body's total iron content, about  400 mg  is devoted to cellular proteins that use iron for important cellular processes like storing oxygen (myoglobin) or performing energy-producing redox reactions ( cytochromes ). A relatively small amount (3–4 mg) circulates through the  plasma , bound to transferrin. [ 9 ]  Because of its toxicity, free soluble iron is kept in low concentration in the body.


Iron deficiency  first affects the storage of iron in the body, and depletion of these stores is thought to be relatively asymptomatic, although some vague and  non-specific symptoms  have been associated with it. Since iron is primarily required for hemoglobin,  iron deficiency anemia  is the primary clinical manifestation of iron deficiency. Iron-deficient people will suffer or die from organ damage well before their cells run out of the iron needed for intracellular processes like electron transport.


Macrophages  of the  reticuloendothelial system  store iron as part of the process of breaking down and processing hemoglobin from engulfed red blood cells. Iron is also stored as a pigment called  hemosiderin , which is an ill-defined deposit of protein and iron, created by macrophages where excess iron is present, either locally or systemically, e.g., among people with iron overload due to frequent blood cell destruction and the necessary transfusions their condition calls for. If systemic iron overload is corrected, over time the hemosiderin is slowly resorbed by the macrophages.


Human iron homeostasis is regulated at two different levels. Systemic iron levels are balanced by the controlled absorption of dietary iron by  enterocytes , the cells that line the interior of the  intestines , and the uncontrolled loss of iron from epithelial sloughing, sweat, injuries and blood loss. In addition, systemic iron is continuously recycled. Cellular iron levels are controlled differently by different cell types due to the expression of particular iron regulatory and transport proteins.


The absorption of dietary iron is a variable and dynamic process. The amount of iron absorbed compared to the amount ingested is typically low, but may range from 5% to as much as 35% depending on circumstances and type of iron. The efficiency with which iron is absorbed varies depending on the source. Generally, the best-absorbed forms of iron come from animal products. Absorption of dietary iron in iron salt form (as in most supplements) varies somewhat according to the body's need for iron, and is usually between 10% and 20% of iron intake. Absorption of iron from animal products, and some plant products, is in the form of heme iron, and is more efficient, allowing absorption of from 15% to 35% of intake. Heme iron in animals is from blood and heme-containing proteins in meat and mitochondria, whereas in plants, heme iron is present in mitochondria in all cells that use oxygen for respiration.


Like most mineral nutrients, the majority of the iron absorbed from digested food or supplements is absorbed in the  duodenum  by  enterocytes  of the duodenal lining. These cells have special molecules that allow them to move iron into the body. To be absorbed, dietary iron can be absorbed as part of a protein such as heme protein or iron must be in its ferrous Fe 2+  form. A ferric reductase enzyme on the enterocytes'  brush border , duodenal cytochrome B ( Dcytb ), reduces ferric Fe 3+  to Fe 2+ . [ 10 ]  A protein called divalent metal transporter 1 ( DMT1 ), which can transport several  divalent  metals across the plasma membrane, then transports iron across the enterocyte's  cell membrane  into the cell. If the iron is bound to heme, it is instead transported across the apical membrane by  heme carrier protein 1  (HCP1). [ 11 ]  Heme is then  catabolized  by microsomal  heme oxygenase  into  biliverdin , releasing Fe 2+ . [ 12 ]


These intestinal lining cells can then either store the iron as  ferritin , which is accomplished by Fe 2+  binding to apoferritin (in which case the iron will leave the body when the cell dies and is sloughed off into  feces ), or the cell can release it into the body via the only known iron exporter in mammals,  ferroportin .  Hephaestin , a  ferroxidase  that can oxidize Fe 2+  to Fe 3+  and is found mainly in the small intestine, helps ferroportin transfer iron across the basolateral end of the intestine cells. Upon release into the bloodstream, Fe 3+  binds transferrin and circulates to tissues. In contrast, ferroportin is post-translationally repressed by  hepcidin , a 25-amino acid peptide hormone. The body regulates iron levels by regulating each of these steps. For instance, enterocytes synthesize more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia. [ 13 ]  Iron absorption from diet is enhanced in the presence of vitamin C and diminished by excess calcium, zinc, or manganese. [ 14 ]


The human body's rate of iron absorption appears to respond to a variety of interdependent factors, including total iron stores, the extent to which the bone marrow is producing new red blood cells, the concentration of hemoglobin in the blood, and the oxygen content of the blood. The body also absorbs less iron during times of  inflammation , in order to deprive bacteria of iron. Recent discoveries demonstrate that hepcidin regulation of ferroportin is responsible for the syndrome of anemia of chronic disease.


Most of the iron in the body is hoarded and recycled by the reticuloendothelial system, which breaks down aged red blood cells. In contrast to iron uptake and recycling, there is no physiologic regulatory mechanism for  excreting  iron. People lose a small but steady amount by gastrointestinal blood loss, sweating and by shedding cells of the skin and the  mucosal  lining of the  gastrointestinal tract . The total amount of loss for healthy people in the developed world amounts to an estimated average of  1 mg  a day for men, and 1.5–2 mg a day for women with regular menstrual periods. [ 15 ]  People with gastrointestinal parasitic infections, more commonly found in developing countries, often lose more. [ 1 ]  Those who cannot regulate absorption well enough get disorders of iron overload. In these diseases, the toxicity of iron starts overwhelming the body's ability to bind and store it. [ 16 ]


Most cell types take up iron primarily through  receptor-mediated endocytosis  via  transferrin receptor 1  (TFR1),  transferrin receptor 2  (TFR2) and  GAPDH . TFR1 has a 30-fold higher affinity for transferrin-bound iron than TFR2 and thus is the main player in this process. [ 17 ] [ 18 ]  The higher order multifunctional glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) also acts as a transferrin receptor. [ 19 ] [ 20 ]  Transferrin-bound ferric iron is recognized by these transferrin receptors, triggering a conformational change that causes endocytosis. Iron then enters the cytoplasm from the endosome via importer DMT1 after being reduced to its ferrous state by a STEAP family reductase. [ 21 ]


Alternatively, iron can enter the cell directly via plasma membrane divalent cation importers such as DMT1 and ZIP14 (Zrt-Irt-like protein 14). [ 22 ]  Again, iron enters the cytoplasm in the ferrous state after being reduced in the extracellular space by a reductase such as STEAP2, STEAP3 (in red blood cells), Dcytb (in enterocytes) and SDR2. [ 21 ]


Iron can also enter cells via  CD44  in complexes bound to  hyaluronic acid  during  epithelial–mesenchymal transition  (EMT). In this process,  epithelial cells  transform into  mesenchymal cells  with detachment from the  basement membrane , to which they’re normally anchored, paving the way for the newly differentiated motile mesenchymal cells to begin migration away from the epithelial layer. [ 23 ] [ 24 ]


While EMT plays a crucial role in physiological processes like  implantation , where it enables the  embryo  to invade the  endometrium  to facilitate  placental  attachment, its dysregulation can also fuel the  malignant  spread of  tumors  empowering them to invade surrounding tissues and establish distant colonies ( metastasis ). [ 24 ]


Malignant cells often exhibit a heightened demand for iron, fueling their transition towards a more invasive mesenchymal state. This iron is necessary for the expression of mesenchymal genes, like those encoding  transforming growth factor beta  (TGF-β), crucial for EMT. Notably, iron’s unique ability to catalyze  protein  and  DNA   demethylation  plays a vital role in this gene expression process. [ 23 ]


Conventional iron uptake pathways, such as those using the transferrin receptor 1 (TfR1), often prove insufficient to meet these elevated iron demands in cancer cells. As a result, various  cytokines  and  growth factors  trigger the upregulation of CD44, a surface molecule capable of internalizing iron bound to the hyaluronan complex. This alternative pathway, relying on CD44-mediated endocytosis, becomes the dominant iron uptake mechanism compared to the traditional TfR1-dependent route. [ 23 ] [ 24 ]


In the cytoplasm, ferrous iron is found in a soluble, chelatable state which constitutes the labile iron pool (~0.001 mM). [ 25 ]  In this pool, iron is thought to be bound to low-mass compounds such as peptides, carboxylates and phosphates, although some might be in a free, hydrated form ( aqua ions ). [ 25 ]  Alternatively, iron ions might be bound to specialized proteins known as  metallochaperones . [ 26 ]  Specifically, poly-r(C)-binding proteins  PCBP1  and  PCBP2  appear to mediate transfer of free iron to ferritin (for storage) and  non-heme iron enzymes  (for use in catalysis). [ 22 ] [ 27 ]  The labile iron pool is potentially toxic due to iron's ability to generate reactive oxygen species. Iron from this pool can be taken up by mitochondria via  mitoferrin  to synthesize Fe-S clusters and heme groups. [ 21 ]


Iron can be stored in ferritin as ferric iron due to the  ferroxidase  activity of the ferritin heavy chain. [ 28 ]  Dysfunctional ferritin may accumulate as  hemosiderin , which can be problematic in cases of iron overload. [ 29 ]  The ferritin storage iron pool is much larger than the labile iron pool, ranging in concentration from 0.7 mM to 3.6 mM. [ 25 ]


Iron export occurs in a variety of cell types, including  neurons , red blood cells, hepatocytes, macrophages and enterocytes. The latter two are especially important since systemic iron levels depend upon them. There is only one known iron exporter,  ferroportin . [ 30 ]  It transports ferrous iron out of the cell, generally aided by  ceruloplasmin  and/or  hephaestin  (mostly in enterocytes), which oxidize iron to its ferric state so it can bind ferritin in the extracellular medium. [ 21 ]   Hepcidin  causes the internalization of ferroportin, decreasing iron export. Besides, hepcidin seems to downregulate both TFR1 and DMT1 through an unknown mechanism. [ 31 ]  Another player assisting ferroportin in effecting cellular iron export is GAPDH. [ 32 ]  A specific post translationally modified isoform of GAPDH is recruited to the surface of iron loaded cells where it recruits apo-transferrin in close proximity to ferroportin so as to rapidly chelate the iron extruded. [ 33 ]


The expression of hepcidin, which only occurs in certain cell types such as  hepatocytes , is tightly controlled at the transcriptional level and it represents the link between cellular and systemic iron homeostasis due to hepcidin's role as "gatekeeper" of iron release from enterocytes into the rest of the body. [ 21 ]   Erythroblasts  produce  erythroferrone , a hormone which inhibits hepcidin and so increases the availability of iron needed for hemoglobin synthesis. [ 35 ]


Although some control exists at the transcriptional level, the regulation of cellular iron levels is ultimately controlled at the translational level by  iron-responsive element-binding proteins  IRP1 and especially IRP2. [ 36 ]  When iron levels are low, these proteins are able to bind to  iron-responsive elements  (IREs). IREs are stem loop structures in the untranslated regions (UTRs) of mRNA. [ 21 ]


Both ferritin and ferroportin contain an IRE in their 5' UTRs, so that under iron deficiency their translation is repressed by IRP2, preventing the unnecessary synthesis of storage protein and the detrimental export of iron. In contrast, TFR1 and some DMT1 variants contain 3' UTR IREs, which bind IRP2 under iron deficiency, stabilizing the mRNA, which guarantees the synthesis of iron importers. [ 21 ]


Functional or actual iron deficiency can result from a variety of causes. These causes can be grouped into several categories:


The body is able to substantially reduce the amount of iron it absorbs across the mucosa. It does not seem to be able to entirely shut down the iron transport process. Also, in situations where excess iron damages the intestinal lining itself (for instance, when children eat a large quantity of iron tablets produced for adult consumption), even more iron can enter the bloodstream and cause a potentially deadly syndrome of iron overload. Large amounts of free iron in the circulation will cause damage to critical cells in the liver, the  heart  and other metabolically active organs.


Iron toxicity results when the amount of circulating iron exceeds the amount of transferrin available to bind it, but the body is able to vigorously regulate its iron uptake. Thus, iron toxicity from ingestion is usually the result of extraordinary circumstances like iron tablet over-consumption [1] [ 42 ]  rather than variations in  diet . The type of acute toxicity from iron ingestion causes severe mucosal damage in the gastrointestinal tract, among other problems.


Excess iron has been linked to higher rates of disease and mortality. For example, breast cancer patients with low  ferroportin  expression (leading to higher concentrations of intracellular iron) survive for a shorter period of time on average, while high ferroportin expression predicts 90% 10-year survival in breast cancer patients. [ 43 ]  Similarly, genetic variations in iron transporter genes known to increase serum iron levels also reduce  lifespan  and the average number of years spent in good health. [ 44 ]  It has been suggested that mutations that increase iron absorption, such as the ones responsible for hemochromatosis (see below), were selected for during  Neolithic  times as they provided a  selective advantage  against iron-deficiency anemia. [ 45 ]  The increase in systemic iron levels becomes pathological in old age, which supports the notion that  antagonistic pleiotropy  or "hyperfunction" drives human aging. [ 44 ]


Chronic iron toxicity is usually the result of more chronic iron overload syndromes associated with genetic diseases, repeated transfusions or other causes. In such cases the iron stores of an adult may reach 50 grams (10 times normal total body iron) or more. The most common diseases of iron overload are  hereditary hemochromatosis  (HH), caused by mutations in the  HFE  gene, and the more severe disease  juvenile hemochromatosis  (JH), caused by mutations in either  hemojuvelin  ( HJV ) [ 46 ]  or hepcidin ( HAMP ). The exact mechanisms of most of the various forms of adult hemochromatosis, which make up most of the genetic iron overload disorders, remain unsolved. So, while researchers have been able to identify genetic mutations causing several adult variants of hemochromatosis, they now must turn their attention to the normal function of these mutated genes.


Hydremia  (or  Hydraemia ) is a  blood disorder  characterized by excessive fluid volume with or without reduction of  blood plasma  volume. [ 1 ]


This article about a disease of the blood or immune system is a  stub . You can help Wikipedia by  expanding it .


Hypervascularity  is an increased number or  concentration  of  blood vessels .


In  Graves disease , the thyroid gland is hypervascular, which can help in differentiating the condition from  thyroiditis . [ 1 ]


90% of  thyroid papillary carcinoma  cases are hypervascular. [ 2 ]


This  cardiovascular system  article is a  stub . You can help Wikipedia by  expanding it .


Immunohematology  is a branch of  hematology  and  transfusion medicine  which studies  antigen - antibody  reactions and analogous phenomena as they relate to the pathogenesis and clinical manifestations of  blood disorders .  A person employed in this field is referred to as an immunohematologist or colloquially as a blood banker. Their day-to-day duties include  blood typing ,  cross-matching  and  antibody  identification. [ 1 ] [ citation needed ]


Immunohematology and Transfusion Medicine is a medical post graduate specialty in many countries. The specialist Immunohematology and Transfusion Physician provides expert opinion for difficult transfusions, massive transfusions, incompatibility work up, therapeutic  plasmapheresis ,  cellular therapy , irradiated blood therapy, leukoreduced and washed blood products, stem cell procedures, platelet rich plasma therapies,  HLA  and cord blood banking. Other research avenues are in the field of stem cell researches, regenerative medicine and cellular therapy. [ 1 ]


Immunohematology is one of the specialized branches of medical science. It deals with the concepts and clinical 2 techniques related to modern transfusion therapy. Efforts to save human lives by transfusing blood have been recorded for several centuries. The era of blood transfusion, however, really began when William Harvey described the circulation of blood in 1616.


This  immunology  article is a  stub . You can help Wikipedia by  expanding it .


Immunophenotyping  is a technique used to study the protein expressed by cells. This technique is commonly used in basic science research and laboratory diagnostic purpose.  This can be done on tissue section (fresh or fixed tissue),  cell suspension , etc.  An example is the detection of  tumor markers , such as in the  diagnosis  of  leukemia . It involves the labelling of  white blood cells  with  antibodies  directed against surface  proteins  on their membrane. By choosing appropriate antibodies, the differentiation of  leukemic  cells can be accurately determined. The labelled cells are processed in a  flow cytometer , a laser-based instrument capable of analyzing thousands of cells per second. The whole procedure can be performed on cells from the  blood ,  bone marrow  or  spinal fluid  in a matter of a few hours. [ citation needed ]


Immunophenotyping is a very common flow cytometry test in which fluorophore-conjugated antibodies are used as probes for staining target cells with high avidity and affinity. This technique allows rapid and easy phenotyping of each cell in a heterogeneous sample according to the presence or absence of a protein combination.  [ 1 ]


The  International Prognostic Index  ( IPI ) is a clinical tool developed by  oncologists  to aid in predicting the  prognosis  of patients with aggressive  non-Hodgkin's lymphoma .  Previous to IPI's development, the primary consideration in assessing prognosis was the  Ann Arbor stage  alone, but this was increasingly found to be an inadequate means of predicting survival outcomes, and so other factors were studied. [ citation needed ]


In 1984, the first prognostic indicator for advanced non-Hodkin's lymphoma was developed. An information theory guided, computer search and evaluation procedure  entropy minimax  was employed to discover the largest sub-groupings for which survival is as extreme as possible [ 1 ]  In the clinical trials analyzed retrospectively and containing a large fraction of patients not matching the 'good' - of 'good' (Karnofsky status >80 and 'A" Symptoms and SGOT <36 U/L), 'poor' (Karnofsky status <70 or Night sweats) and 'intermediate' (All Remaining) prognosis patterns identified, a significant difference was found between the survival of patients with and those without a complete response to therapy.  The authors concluded that trials using a patient mix weighted toward good prognosis will not find such a difference.


In 1993, a retrospective analysis was performed on 2031 patients with aggressive non-Hodgkin's lymphoma, of all ages, treated with a  doxorubicin -based chemotherapy regimen such as  CHOP  between 1982 and 1987. [ 2 ]  Several patient characteristics were analyzed to determine whether they were associated with differences in survival, and the factors that emerged as significant were, in addition to the Ann Arbor stage: age, elevated serum  lactate dehydrogenase  (LDH),  performance status , and number of extranodal sites of disease.


One point is assigned for each of the following risk factors: [ citation needed ]


The sum of the points allotted correlates with the following risk groups:


A simplified index can be used when comparing patients within an age group (i.e. 60 or younger, or over 60) and includes only 3 of the above factors: [ citation needed ]


Although the IPI has shown itself to be a useful clinical tool, widely used by oncologists and a mainstay of risk stratification in clinical trials for lymphoma, it should be kept in mind that it was developed prior to the use of  rituximab , which is now included with anthracycline-based combination chemotherapy as of the standard of care in  B-cell  lymphomas (the majority of non-Hodgkin's lymphomas). Rituximab has significantly improved the outcomes of lymphoma patients; and its effect on the prognostic value of the IPI is uncertain.  Future development of a more rigorous prognostic index may thus be useful.


Given the success of the IPI for intermediate grade lymphomas, an effort was undertaken to develop a similar prognostic index for the most common low-grade lymphoma,  follicular lymphoma . The prognostic factors that emerged from this were: age, stage, number of lymph node areas involved, serum  hemoglobin  level, and serum LDH. [ 3 ]


One point is assigned for each of the following adverse prognostic factors: [ citation needed ]


An effort was more recently undertaken to identify a similar prognostic index predictive of outcome in advanced mantle cell lymphoma. There were four factors found to have independent prognostic relevance: age, performance status, LDH, and white blood cell count (WBC). [ 4 ]


The point values are assigned as follows:


The sum of the allotted points correlates with the following risk groups:


Intravascular hemolysis  describes  hemolysis  that happens mainly inside the  vasculature . [ 1 ]  As a result, the contents of the red blood cell are released into the general circulation, leading to  hemoglobinemia [ 2 ]  and increasing the risk of ensuing  hyperbilirubinemia . [ 3 ]


Intravascular hemolysis is the state when the red blood cell ruptures as a result of the complex of complement autoantibodies attached (fixed) on the surfaces of RBCs attack and rupture RBCs' membranes, or a parasite such as  Babesia  exits the cell that ruptures the RBC's membrane as it goes. [ 4 ]


Upon RBC's rupture, components of which are released and circulating in the blood plasma. [ 3 ]


These components comprise hemoglobin and others. [ 3 ]  At this stage, the hemoglobin is called  free hemoglobin . [ 3 ]  Free hemoglobin (also called  naked hemoglobin ) is the un-bound hemoglobin that is not enclosed in the red blood cell. The naked hemoglobin is devoid of its anti-oxidant sentries that are normally available within the RBC. [ 5 ]  Free hemoglobin is thus vulnerable to be oxidized. [ 5 ]


When the serum concentration of free hemoglobin is within the physiologic range of  haptoglobin , the potential deleterious effects of free hemoglobin are prevented because haptoglobin will bind to "free hemoglobin" forming a complex of "free hemoglobin-haptoglobin" evidenced by reduced amount of haptoglobin. [ 6 ]  However, during hyper-hemolytic conditions or with chronic hemolysis, haptoglobin is depleted so the remaining free hemoglobin readily distribute to tissues where it might be exposed to oxidative conditions, [ 2 ]  thus some of the ferrous heme (FeII), the oxygen-binding component of hemoglobin, of the free hemoglobin are oxidized and becoming  met-hemoglobin  (ferric hemoglobin). [ 2 ]  In such conditions, heme along with globin chains can be released from further oxidization of met-hemoglobin (ferric Hb). [ 2 ]  In which, the free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. At this time,  hemopexin , another plasma glycoprotein come to bind with heme with its privilege of high heme affinity, forming a complex of heme-hemopexin, which is non-toxic, and travel together to a receptor on hepatocytes and macrophages within the spleen, liver and bone marrow. [ 7 ] [ 2 ]  (Note that the "free hemoglobin-haptoglobin" complex is taken up by hepatocytes and, to the lesser extent, macrophages. [ 2 ] ) Thereafter, these complexes will undergo the metabolic mechanisms like extravascular hemolysis. [ 6 ]


Nevertheless, if the binding capacities of haptoglobin and hemopexin are saturated [ note 1 ] , the remaining "free hemoglobin" in the plasma will be oxidized to met-hemoglobin eventually, and then further disassociates into free heme and others. [ 3 ]  At this stage, the "free heme" will bind to albumin, forming  met-hemalbumin . [ 3 ] [ 8 ]  As to the remaining unbound (met)hemoglobin is filtered into the primary urine and re-absorbed via  proximal tubules  of the kidney. [ 3 ]  In proximal tubules, the iron is extracted and stored as  hemosiderin . [ 3 ]  (Long-term hemoglobinuria is associated with substantial deposition of hemosiderin in proximal tubule (excessive accumulation of hemosiderin in proximal tubule),  Fanconi syndrome  (damaged renal re-absorption capability of small molecules which give rises to hyper- aminoaciduria ,  glycosuria ,  hyperphosphaturia , and  bicarbonate  and  dehydration ), and  chronic kidney failure . [ 6 ] )


In the end, if the plasma concentration of the "free met-hemoglobin" and/or "free hemoglobin" is still too high for proximal tubule to absorb back into the body, then  hemoglobinuria  occurs, [ 3 ]  indicating an extensive intravascular hemolysis. [ 3 ]  These remaining free hemoglobin entities also begin to consume  nitric oxide , which is critical regulators of vascular homeostasis and basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation. [ 6 ]  The reduction of nitric oxide deeply disturbs the body's mechanism to maintain the stability of the hemodynamics. [ 6 ]  Additionally, free hemoglobin manifests direct cytotoxic, inflammatory, and pro-oxidant effects that in turn negatively impact endothelial function. [ 6 ]  At the meantime, free heme exerts its multiple pro-inflammatory and pro-oxidant effects to the tissues it goes through. [ 6 ]


It is important to note that although hemosiderins are also included in the urine in the setting of intravascular hemolytic hemoglobinuria, [ 3 ]  it will be detected only several days after the onset of the extensive intravascular hemolysis and will remain detectable several days after termination of intravascular hemolysis. [ 3 ]  The phenomenon tells that the detection of hemosiderin in urine is indicative of either ongoing or recent intravascular hemolysis characterized by excessive hemoglobin and/or met-hemoglobin filtered through the  renal glomerulus  as well as the loss of  hemosiderin-laden necrotic tubular cells . [ 3 ]


2PMV ,  3KQ4


Intrinsic factor  ( IF ),  cobalamin binding intrinsic factor , [ 5 ]  also known as  gastric intrinsic factor  ( GIF ), is a  glycoprotein  produced by the  parietal cells  (in humans) or chief cells (in rodents) of the  stomach . It is necessary for the absorption of  vitamin B 12  later on in the distal  ileum  of the  small intestine . [ 6 ]  In humans, the gastric intrinsic factor  protein  is encoded by the  CBLIF   gene . [ 5 ]   Haptocorrin  ( transcobalamin I ) is another glycoprotein secreted by the  salivary glands  which binds to  vitamin B 12 . Vitamin B 12  is acid-sensitive and in binding to haptocorrin it can safely pass through the acidic stomach to the duodenum. [ 7 ]


In the less acidic environment of the  small intestine , pancreatic enzymes digest the glycoprotein carrier and vitamin B 12  can then bind to intrinsic factor. [ 7 ]  This new complex is then absorbed by the epithelial cells ( enterocytes ) of the  ileum . [ 7 ]  Inside the cells, vitamin B 12  dissociates once again and binds to another protein,  transcobalamin II ; the new complex can then exit the epithelial cells to be carried to the liver. [ 8 ]


Intrinsic factor is secreted by  parietal cells  within the stomach, and so is present in the gastric juice as well as in the  gastric mucous membrane . [ 9 ]  The optimum pH for its action is approximately 7. [ 10 ]  Its concentration does not correlate with the amount of  HCl  or  pepsin  in the gastric juice, e.g., intrinsic factor may be present even when pepsin is largely absent. [ 11 ]  The site of formation of the intrinsic factor varies in different species. In pigs it is obtained from the  pylorus  and beginning of the  duodenum ; [ 12 ]   in human beings it is present in the  fundus  and body of the  stomach . [ 13 ]


The limited amount of normal human gastric intrinsic factor limits normal efficient absorption of B 12  to about 2 μg per meal, a nominally adequate intake of B 12 . [ 14 ]


In  pernicious anemia , which is usually an  autoimmune disease ,  autoantibodies  directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency,  malabsorption  of vitamin B 12 , and subsequent  megaloblastic anemia . [ 15 ]   Atrophic gastritis  can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall. [ 16 ]   Pancreatic exocrine insufficiency  can interfere with normal dissociation of vitamin B 12  from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex. [ 17 ]  Other risk factors contributing to pernicious anemia are anything that damages or removes a portion of the stomach's parietal cells, including  bariatric surgery , gastric tumors, gastric ulcers, and excessive consumption of alcohol. [ citation needed ]


Mutations in the  GIF  gene are responsible for a rare inheritable disease called  intrinsic factor deficiency [ 18 ]  which results in malabsorption of vitamin B 12 . [ 19 ]


In most countries,  intramuscular injections  of vitamin B 12  are used to treat  pernicious anemia . [ 20 ]  Orally administered vitamin B 12  is absorbed without intrinsic factor, but at levels of less than one percent than if intrinsic factor is present. [ 21 ]   Despite the low amounts absorbed, oral vitamin B 12  therapy is effective at reducing symptoms of pernicious anemia. [ 22 ]


Vitamin B 12  can also be given  sublingually , but there is no evidence that this route of administration is superior to the oral route, [ 23 ]  and only Canada and Sweden routinely prescribe this route of administration. [ 20 ]


Because vitamin B 12  absorption is a multistep process that involves the stomach, pancreas and small intestine, and is mediated by two carriers:  Haptocorrin  and intrinsic factor, and because  Haptocorrin  ( transcobalamin I ) binds to vitamin B 12 , and  Vitamin B 12  is acid-sensitive, when vitamin B 12  binds to  Haptocorrin  it can safely pass through the acidic stomach to the duodenum, given time in the mouth. [ 7 ]


Iptacopan , sold under the brand name  Fabhalta , is a  medication  used for the treatment of  paroxysmal nocturnal hemoglobinuria (PNH) . [ 3 ]  It is a  complement factor B  inhibitor that was developed by  Novartis . [ 3 ]  It is taken  by mouth . [ 3 ]


Iptacopan was approved by the US  Food and Drug Administration  (FDA) for the treatment of adults with paroxysmal nocturnal hemoglobinuria in December 2023. [ 5 ] [ 6 ]  The FDA considers it to be a  first-in-class medication . [ 7 ]


Iptacopan is  indicated  for the treatment of adults with paroxysmal nocturnal hemoglobinuria. [ 3 ] [ 8 ]


Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, generation of downstream effectors, and the amplification of the terminal pathway. [ 9 ]


In  PNH ,  intravascular hemolysis  (IVH) is mediated by the downstream membrane attack complex (MAC), while  extravascular hemolysis  (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement mediated IVH. [ 9 ]


The FDA label for iptacopan contains a  black box warning  for the risk of serious and life-threatening infections caused by encapsulated bacteria, including  Streptococcus pneumoniae ,  Neisseria meningitidis , and  Haemophilus influenzae  type B. [ 3 ]