Diagnostic work-up supports the differential diagnosis of TMA-causing diseases. A positive Shiga-toxin/EHEC test confirms a cause for STEC-HUS, [ 25 ] [ 27 ]  and severe  ADAMTS13  deficiency (i.e., ≤5% of normal ADAMTS13 levels) confirms a diagnosis of TTP. [ 48 ]


The effect of antibiotics in shiga toxin producing  E. coli  is unclear. [ 1 ]  While some early studies raised concerns more recent studies show either no effect or a benefit. [ 1 ]


Treatment involves  supportive care  and may include  dialysis ,  steroids ,  blood transfusions , and  plasmapheresis . [ 1 ] [ 2 ]  Early  IV fluid  hydration is associated with better outcomes including shorter hospital stays and reducing the risk of dialysis. [ 34 ]


Empiric antibiotics are not indicated in those who are immunocompetent, and may worsen the HUS. [ 34 ]   Antidiarrheals  and narcotic medications to slow the gut are not recommended as they are associated with worsening symptoms, increased risk of HUS in those with STEC infection, and adverse neurologic reactions. [ 34 ]  Platelet transfusions should not be used as the may drive the process of microangiopathy leading to worsening TTP. [ 34 ]


While  eculizumab  is being used to treat atypical hemolytic uremic syndrome, no evidence as of 2018 supports its use in the main forms of HUS. [ 1 ]  Scientists are trying to understand how useful it would be to immunize humans or cattle. [ 49 ]


Acute renal failure occurs in 55–70% of people with STEC-HUS, although up to 70–85% recover renal function. [ 50 ]  With aggressive treatment, more than 90% of patients survive the acute phase of HUS, and only about 9% may develop ESRD. Roughly one-third of persons with HUS have abnormal kidney function many years later, and a few require long-term dialysis. Another 8% of persons with HUS have other lifelong complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of having part of their colon removed. STEC-HUS is associated with a 3% mortality rate among young children and a 20% mortality rate in middle age or older adults. [ 34 ]  15-20% of children infected with STEC develop HUS, with the highest risk being in children younger than 5 years old. [ 34 ]


Patients with aHUS generally have poor outcomes, with up to 50% progressing to  end-stage renal disease  (ESRD) or irreversible brain damage; as many as 25% die during the acute phase. [ 50 ]


HUS is now considered as a part of the broader group of Thrombotic microangiopathies (TMA).  Thrombotic thrombocytopenic purpura  (TTP), a TMA, was first described by the Hungarian born, American pathologist and physician  Eli Moschcowitz  (1879–1964). In 1924, [ 51 ]  Moschcowitz first described TTP as a distinct clinicopathologic condition that can mimic the clinical characteristics of Hemolytic–uremic syndrome (HUS). That was in a 16-year-old girl who died 2 weeks after the abrupt onset and progression of petechial bleeding, pallor, fever, paralysis, hematuria and coma; and called "Moschcowitz disease". [ 52 ] [ 53 ]  Moreover, Moschcowitz was among the first to work in psychosomatic medicine, and he presented a paper in 1935 on the psychological origins of physical disease. HUS was first described by Conrad Gasser in 1955, and the systemic character of HUS was subsequently defined. [ 54 ]  Bernard Kaplan identified several distinct entities that can manifest as HUS and emphasized that HUS was a syndrome with a common pathologic outcome. Kaplan is a Canadian professor and director of Pediatric Nephrology. He has an international reputation for his studies, over the past 34 years, on the hemolytic uremic syndromes. [ 55 ]  The discovery that endothelial cell injury underlies this broad spectrum of TMA disorders has come into focus during the last two decades. In the 1980s, Mohamed Karmali (1945–2016) was the first to make the association between Stx, diarrheal E. coli infection and the idiopathic hemolytic uremic syndrome of infancy and childhood. Karmali's work showed that the hemolytic uremic syndrome the children in Canada was caused by this particular bacteria. Karmali also developed the system of classifying strains of E.coli and determining which cause disease in humans. He defined the presence of microvascular injury in diarrhea-associated HUS and the critical role of a verotoxin produced by specific strains of Escherichia coli. [ 56 ]  This verotoxin was subsequently found to be a member of a family of toxins first identified with Shigella and known as Shiga toxin (Stx). [ 57 ]  This relationship and the eventual link of TTP to abnormally high levels of ultra-large Von Willebrand factor (vWF) multimers caused by congenital or acquired reductions in ADAMTS13 activity was established at approximately the same time. In 1924, a Finnish physician  Erik Adolf von Willebrand  (1870–1949) was consulted about a young girl with a bleeding disorder. Von Willebrand described this disorder in 1926, distinguishing it from hemophilia. The disorder was named after him, becoming known as von Willebrand disease. The cause of the disease was later discovered to be a deficiency of a protein, now known as von Willebrand factor, that enables hemostasis. Paul Warwicker is an English nephrologist, whilst in Newcastle in the mid-1990s his research in molecular genetics with Professors Tim and Judith Goodship led to the genetic mapping of the familial form of atypical HUS and the descriptions of the first HUS-related mutations and polymorphisms in the factor H gene in both familial and sporadic HUS. He was awarded an MD in molecular genetics in 2000, and elected fellow of the Royal College of Physicians in the same year. [ 58 ]  Paul Warwicker confirmed the association of atypical HUS (aHUS) to defects in a region on chromosome 1 that contains the genes for several complement regulatory proteins. [ 59 ]  Later, mutations in complement factor H, complement factor I, membrane cofactor protein, factor B, C3, and thrombomodulin have now been found to cause many of the familial cases of aHUS. These discoveries have allowed a more comprehensive understanding of the pathogenesis, evaluation, and treatment of the entire spectrum of TMA disorders and provide a more rational and effective approach to the care of these children with complicated disease. Prior to the use of monoclonal antibodies patients with aHUS had an extremely poor prognosis. Eculizumab (Soliris®, Alexion Pharmaceuticals, Inc., Boston, MA, USA) is a humanized monoclonal complement inhibitor that is the first and only approved treatment for patients with aHUS by FDA in September 2011. Eculizumab binds with high affinity to C5, inhibiting C5 cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9, thus inhibiting complement-mediated TMA. Eculizumab was proven to be effective in patients with aHUS in which it resolved and prevented complement-mediated TMA, improving renal function and hematologic outcomes. [ 60 ]  Alexion head of R&D 'John Orloff, M.D. "The results met the high bar of complete TMA response, defined by hematologic normalization and improved kidney function," said Alexion R&D head John Orloff, M.D., who reckons the drug can become the "new standard of care for patients with aHUS." "We are preparing regulatory submissions for Ultomiris in aHUS in the U.S., European Union and Japan as quickly as possible," he added. [ 61 ]


The country with the highest incidence of HUS is Argentina [ 62 ] [ 63 ] [ 64 ] [ 65 ]  and it performs a key role in the research of this condition.


In the United States, the overall incidence of HUS is estimated at 2.1 cases per 100,000 persons/year, with a peak incidence between six months and four years of age. [ 66 ]


HUS and the  E. coli  infections that cause it have been the source of much negative publicity for the FDA, meat industries, and fast-food restaurants since the 1990s, especially in the contaminations linked to Jack in the Box restaurants. In 2006, an epidemic of harmful  E. coli  emerged in the United States due to contaminated spinach. In June 2009,  Nestlé  Toll House cookie dough was linked to an outbreak of  E. coli  O157:H7 in the United States, which sickened 70 people in 30 states. [ 66 ]


In May 2011 an  epidemic  of bloody diarrhea caused by  E. coli  O104:H4-contaminated  fenugreek  seeds hit Germany. Tracing the epidemic revealed more than 3,800 cases, with HUS developing in more than 800 of the cases, including 36 fatal cases. Nearly 90% of the HUS cases were in adults. [ 67 ] [ 68 ]


Hepatic veno-occlusive disease  ( VOD ) or  veno-occlusive disease with immunodeficiency  is a potentially life-threatening condition in which some of the small  veins  in the  liver  are obstructed. It is a  complication  of high-dose  chemotherapy  given before a  bone marrow transplant  or excessive exposure to hepatotoxic  pyrrolizidine alkaloids . It is classically marked by weight gain due to  fluid retention ,  increased liver size , and raised levels of  bilirubin  in the blood. [ 1 ]  The name  sinusoidal obstruction syndrome  ( SOS ) is preferred if hepatic veno-occlusive disease happens as a result of chemotherapy or bone marrow transplantation. [ 1 ] [ 2 ]


Apart from chemotherapy, hepatic veno-occlusive disease may also occur after ingestion of certain plant  alkaloids  such as pyrrolizidine alkaloids (in some herbal teas), [ 1 ]  and has been described as part of a rare  hereditary disease  called  hepatic venoocclusive disease with immunodeficiency  (which results from mutations in the gene coding for a protein called  SP110 ). [ 3 ]


Features of hepatic veno-occlusive disease include weight gain, tender  enlargement of the liver ,  ascites , and  yellow discoloration of the skin ; it often is associated with  acute kidney failure . [ 4 ]


In the bone marrow transplant setting, hepatic veno-occlusive disease is felt to be due to injury to the hepatic venous endothelium from the conditioning regimen. Toxic agents causing veno-occlusive disease include plants as well as the medication  cyclophosphamide . [ citation needed ]


Doppler  ultrasound  of the liver is typically utilized to confirm or suggest the diagnosis. Common findings on liver doppler ultrasound include increased phasicity of portal veins with eventual development of portal flow reversal. The liver is usually enlarged but maintained normal  echogenicity . A  liver biopsy  is required for a definitive diagnosis. [ citation needed ]


Treatment generally includes  supportive care  including pain management and possibly  diuretics . [ 5 ]  In those with severe disease due to a bone marrow transplant,  defibrotide  is a proposed treatment. [ 6 ]  It has been approved for use in severe cases in Europe and the United States. [ 7 ] [ 8 ]  A  placebo controlled trial , however, has not been done as of 2016. [ 5 ]


Mild disease has a risk of death of about 10% while moderate disease has a risk of death of 20%. [ 5 ]  When it occurs as a result of bone marrow transplant and multiorgan failure is present, the risk of death is greater than 80%. [ 6 ]


The first report on veno-occlusive disease, in 1920, was as a result of  senecio  poisoning in  South Africa . [ 9 ]  Subsequent reports were mostly in Jamaicans who had consumed herbal teas. [ 1 ]  With the advent of bone marrow transplantation, most cases since its introduction have been in those undergoing treatment for  leukemia . [ 1 ]


Hyperviscosity syndrome  is a group of symptoms triggered by an increase in the  viscosity  of the  blood . Symptoms of high  blood viscosity  include spontaneous bleeding from  mucous membranes , visual disturbances due to  retinopathy , and neurologic symptoms ranging from  headache  and  vertigo  to  seizures  and  coma .


Hyperviscosity occurs from pathologic changes of either cellular or protein fractions of the blood such as is found in  polycythemias ,  multiple myeloma  (particularly IgA and IgG3),  leukemia ,  monoclonal gammopathies  such as  Waldenström macroglobulinemia ,  sickle cell anemia , and  sepsis . [ citation needed ]


Types of hyperviscosity syndromes vary by pathology; including  serum  hyperviscosity, which may cause neurologic or ocular disorders; polycythemic hyperviscosity, which results in reduced blood flow or capillary  perfusion  and increased organ congestion; and syndromes of hyperviscosity, caused by reduced  deformability  of  red blood cells , often evident in sickle cell anemia. [ 1 ]


High cell counts are seen in conditions such as  polycythemia  (raised red blood cells) or  leukemia  (more  white blood cells , especially in  acute leukemia blast crises ).


May occur with a white blood cell count greater than 100,000/mm 3  (100×10 9 /L). [ 2 ]


Although elevated whole blood viscosity is a better measure of hyperviscosity and more common and clinically important, serum viscosity and plasma viscosity are more frequently measured. [ 3 ]  Normal plasma viscosity is between 1.4 and 1.8  centipoise  while symptoms from hyperviscosity typically occur greater than 4 centipoise (about 4 times more viscous than water) and require emergency treatment. [ 3 ]


Patients will also have evidence of their underlying disorder. Those with   myeloma  will typically display a  rouleaux  formation on a peripheral smear and a large  globulin  gap, indicative of a significant  paraprotein  load. Although it used to be the case that test results would take a few days to return, the development of a new generation of automated clinical viscometers means that results can now be obtained within minutes, allowing accurate diagnosis and more targeted therapy. If hyperviscosity is confirmed, treatment can commence early on in the diagnosis. [ 4 ]  Fundoscopic examination reveals dilation of retinal veins and flame shaped retinal hemorrhages. [ 5 ]


Plasmapheresis  may be used to decrease viscosity in the case of myeloma, whereas  leukapheresis  or  phlebotomy  may be employed in a leukemic or polycythemic crisis, respectively.  Blood transfusions  should be used with caution as they can increase serum viscosity. Hydration is a temporizing measure to employ while preparing pheresis. Even after treatment, the condition will recur unless the underlying disorder is treated. [ citation needed ]  Serum viscosity and electrophoresis are recommended before and after plasmapheresis in order to correlate viscosity and M-spike with patient symptoms. This correlation may be useful for anticipating the need for repeat plasmapheresis. [ 6 ]


Hypovolemia , also known as  volume depletion  or  volume contraction , is a state of abnormally low  extracellular fluid  in the body. [ 1 ]  This may be due to either a loss of both salt and water or a decrease in  blood volume . [ 2 ] [ 3 ]  Hypovolemia refers to the loss of extracellular fluid and should not be confused with  dehydration . [ 4 ]


Hypovolemia is caused by a variety of events, but these can be simplified into two categories: those that are associated with  kidney function  and those that are not. [ 5 ]  The signs and symptoms of hypovolemia worsen as the amount of fluid lost increases. [ 6 ]  Immediately or shortly after mild fluid loss (from  blood donation ,  diarrhea ,  vomiting , bleeding from trauma, etc.), one may experience  headache ,  fatigue ,  weakness ,  dizziness , or  thirst . Untreated hypovolemia or excessive and rapid losses of volume may lead to  hypovolemic shock . [ 7 ]  Signs and symptoms of hypovolemic shock include  increased heart rate ,  low blood pressure ,  pale or cold skin , and  altered mental status . When these signs are seen, immediate action should be taken to  restore the lost volume .


Signs and symptoms of hypovolemia progress with increased loss of fluid volume. [ 5 ]


Early symptoms of hypovolemia include headache, fatigue, weakness, thirst, and dizziness. The more severe signs and symptoms are often associated with hypovolemic shock. These include  oliguria ,  cyanosis , abdominal and chest pain,  hypotension ,  tachycardia , cold hands and feet, and progressively altering mental status. [ citation needed ]


The causes of hypovolemia can be characterized into two categories: [ 5 ]


The signs and symptoms of hypovolemia are primarily due to the consequences of decreased circulating volume and a subsequent reduction in the amount of blood reaching the tissues of the body. [ 9 ]  In order to properly perform their functions, tissues require the oxygen transported in the blood. [ 10 ]  A decrease in circulating volume can lead to a decrease in bloodflow to the brain, resulting in headache and dizziness. [ citation needed ]


Baroreceptors  in the body (primarily those located in the  carotid sinuses  and  aortic arch ) sense the reduction of circulating fluid and send signals to the brain to increase sympathetic response ( see also:  baroreflex ). [ 11 ]  This sympathetic response is to release  epinephrine  and  norepinephrine , which results in peripheral  vasoconstriction  (reducing size of blood vessels) in order to conserve the circulating fluids for organs vital to survival (i.e. brain and heart). Peripheral vasoconstriction accounts for the cold extremities (hands and feet), increased heart rate, increased cardiac output (and associated chest pain). Eventually, there will be less  perfusion  to the kidneys, resulting in decreased urine output. [ citation needed ]


Hypovolemia can be recognized by a  fast heart rate ,  low blood pressure , [ 12 ]  and the absence of  perfusion  as assessed by skin signs (skin turning pale) and/or  capillary refill  on  forehead ,  lips  and  nail beds .  The patient may feel dizzy, faint, nauseated, or very thirsty.  These signs are also characteristic of most types of  shock . [ 13 ]


In children, compensation can result in an artificially high blood pressure despite hypovolemia (a decrease in blood volume). Children typically are able to compensate (maintain blood pressure despite hypovolemia) for a longer period than adults, but deteriorate rapidly and severely once they are unable to compensate ( decompensate ). [ 14 ]  Consequently, any possibility of  internal bleeding  in children should be treated aggressively. [ 15 ] [ 16 ]


Signs of external bleeding should be assessed, noting that individuals can bleed internally without external blood loss or otherwise apparent signs. [ 16 ]


There should be considered possible mechanisms of injury that may have caused internal bleeding, such as ruptured or bruised internal organs. If trained to do so and if the situation permits, there should be conducted a  secondary survey  and checked the chest and abdomen for pain, deformity, guarding, discoloration or swelling.  Bleeding into the abdominal cavity can cause the classical bruising patterns of  Grey Turner's sign  (bruising along the sides) or  Cullen's sign  (around the navel). [ 17 ]


In a hospital, physicians respond to a case of hypovolemic shock by conducting these examinations: [ citation needed ]


Untreated hypovolemia can lead to shock (see also:  hypovolemic shock ). Most sources state that there are 4 stages of hypovolemia and subsequent shock; [ 18 ]  however, a number of other systems exist with as many as 6 stages. [ 19 ]


The 4 stages are sometimes known as the "Tennis" staging of hypovolemic shock, as the stages of blood loss (under 15% of volume, 15–30% of volume, 30–40% of volume and above 40% of volume) mimic the scores in a game of  tennis : 15, 15–30, 30–40 and 40. [ 20 ]  It is basically the same as used in classifying  bleeding  by blood loss. [ citation needed ]


The signs and symptoms of the major stages of hypovolemic shock include: [ 21 ] [ 22 ]


The most important step in treatment of hypovolemic shock is to identify and control the source of bleeding. [ 23 ]


Medical personnel should immediately supply emergency oxygen to increase efficiency of the patient's remaining blood supply. This intervention can be life-saving. [ 24 ]


Also, the respiratory pump is especially important during hypovolemia as spontaneous breathing may help reduce the effect of this loss of blood pressure on stroke volume by increasing venous return. [ 25 ]


The use of  intravenous fluids  (IVs) may help compensate for lost fluid volume, but IV fluids cannot carry oxygen the way blood does—however, researchers are developing  blood substitutes  that can. Infusing  colloid  or  crystalloid  IV fluids also dilutes  clotting factors  in the blood, increasing the risk of bleeding. Current best practice allow  permissive hypotension  in patients with hypovolemic shock, [ 26 ]  both avoid overly diluting clotting factors and avoid artificially raising blood pressure to a point where it "blows off" clots that have formed. [ 27 ] [ 28 ]


Fluid replacement  is beneficial in hypovolemia of stage 2, and is necessary in stage 3 and 4. [ 21 ]  See also the discussion of  shock  and the importance of treating reversible shock while it can still be countered.


The following interventions are carried out: [ citation needed ]


Vasopressors  (such as  dopamine  and  noradrenaline ) should generally be avoided, as they may result in further tissue  ischemia  and don't correct the primary problem. Fluids are the preferred choice of therapy. [ 29 ]


In cases where loss of blood volume is clearly attributable to bleeding (as opposed to, e.g., dehydration), most medical practitioners prefer the term  exsanguination  for its greater specificity and descriptiveness, with the effect that the latter term is now more common in the relevant context. [ 30 ]


The term  leukemoid reaction  describes an increased
 white blood cell  count (> 50,000 cells/μL), which is a physiological response to stress or infection (as opposed to a primary blood  malignancy , such as  leukemia ). It often describes the presence of immature cells such as myeloblasts or red blood cells with nuclei in the peripheral blood.


It may be  lymphoid  or  myeloid . [ 1 ]


As noted above, a leukemoid reaction is typically a response to an underlying medical issue. Causes of leukemoid reactions include: [ citation needed ]


Conventionally, a leukocytosis exceeding 50,000 WBC/mm 3  with a significant increase in early  neutrophil  precursors is referred to as a leukemoid reaction. [ 2 ]  The peripheral blood smear may show  myelocytes ,  metamyelocytes ,  promyelocytes , and rarely  myeloblasts ; however, there is a mixture of early mature neutrophil precursors, in contrast to the immature forms typically seen in  acute leukemia .  Serum leukocyte  alkaline phosphatase  is normal or elevated in leukemoid reaction, but is depressed in  chronic myelogenous leukemia . The  bone marrow  in a leukemoid reaction, if  examined , may be hypercellular but is otherwise typically unremarkable. [ citation needed ]


Leukemoid reactions are generally  benign  and are not dangerous in and of themselves, although they are often a response to a significant disease state (see  Causes  above). However, leukemoid reactions can resemble more serious conditions such as  chronic myelogenous leukemia  (CML), which can present with identical findings on the peripheral blood smear. Historically, various clues including the  leukocyte alkaline phosphatase  score and the presence of  basophilia  were used to distinguish CML from a leukemoid reaction. However, at present the test of choice in adults to distinguish CML is an assay for the presence of the  Philadelphia chromosome , either via  cytogenetics  and  FISH , or via  PCR  for the BCR/ABL fusion gene. The LAP (leukocyte alkaline phosphatase) score is high in reactive states but is low in CML.  In cases where the diagnosis is uncertain, a qualified  hematologist  or  oncologist  should be consulted. [ citation needed ]


Treatment of underlying condition. If drug induced, discontinue drug. If the reaction is found to be from anything besides drug use, certain anti neoplastic drugs may be indicated. [ citation needed ]


aggressive:   Sézary disease


Leukocytosis  is a condition in which the white cell ( leukocyte ) count is above the normal range in the  blood . [ 1 ] [ 2 ]  It is frequently a sign of an  inflammatory response , [ 3 ]  most commonly the result of  infection , but may also occur following certain parasitic infections or  bone tumors  as well as  leukemia . It may also occur after strenuous exercise, convulsions such as epilepsy, emotional stress, pregnancy and labor, anesthesia, as a side effect of medication (e.g.,  lithium ), and epinephrine administration. [ 1 ]  There are five principal types of leukocytosis: [ 4 ]


This increase in leukocyte (primarily neutrophils) is usually accompanied by a  "left upper shift"  in the ratio of immature to mature neutrophils and macrophages. The proportion of immature leukocytes increases due to proliferation and inhibition of granulocyte and monocyte precursors in the bone marrow which is stimulated by several products of inflammation including C3a and G-CSF.
Although it may indicate illness, leukocytosis is considered a laboratory finding instead of a separate  disease .  This classification is similar to that of  fever , which is also a test result instead of a disease. [ citation needed ]
 "Right shift"  in the ratio of immature to mature  neutrophils  is considered with reduced count or lack of "young neutrophils" (metamyelocytes, and  band neutrophils ) in  blood smear , associated with the presence of "giant neutrophils". This fact shows suppression of bone marrow activity, as a hematological sign specific for  pernicious anemia  and  radiation sickness . [ 6 ]


A leukocyte count above 50 × 10 9 / L  is termed a  leukemoid reaction , which is the reaction of a healthy bone marrow to extreme stress, trauma, or infection. It is different from  leukemia  and from  leukoerythroblastosis , in which either immature white blood cells (acute leukemia) or mature, yet non-functional, white blood cells (chronic leukemia) are present in peripheral blood.  [ citation needed ]


Leukocytosis can be subcategorized by the type of white blood cell that is increased in number. Leukocytosis in which  neutrophils  are elevated is  neutrophilia ; leukocytosis in which  lymphocyte  count is elevated is  lymphocytosis ; leukocytosis in which  monocyte  count is elevated is  monocytosis ; and leukocytosis in which  eosinophil  count is elevated is  eosinophilia . [ 7 ]


An extreme form of leukocytosis, in which the WBC count exceeds 100,000/μL, is  leukostasis . In this form there are so many WBCs that clumps of them block  blood flow . This leads to  ischemic  problems including  transient ischemic attack  and  stroke . [ citation needed ]


Leukocytosis is very common in acutely ill patients. It occurs in response to a wide variety of conditions, including viral, bacterial, fungal, or parasitic infection, cancer, hemorrhage, and exposure to certain medications or chemicals including steroids. For lung diseases such as pneumonia and tuberculosis, WBC count is very important for the diagnosis of the disease, as leukocytosis is usually present. [ citation needed ]


The mechanism that causes leukocytosis can be of several forms: an increased release of leukocytes from  bone marrow  storage pools, decreased margination of leukocytes onto vessel walls, decreased  extravasation  of leukocytes from the vessels into tissues, or an increase in number of precursor cells in the marrow. [ 9 ]


Certain medications, including  corticosteroids ,  lithium  and  beta agonists , may cause leukocytosis. [ 10 ]


Leukocytosis is an expected finding in healthy women during the post-partum period and is not a cause for alarm unless accompanied by clinical manifestations of infection. [ 11 ]


Below are  blood reference ranges  for various types of leukocytes/WBCs. [ 12 ]  The 97.5 percentile (right limits in intervals in image, showing 95%  prediction intervals ) is a common limit for defining leukocytosis. [ citation needed ]


While treatment is usually not necessary in the majority of cases, hyperleukocytosis (WBC count > 50 or 100 × 10 9 /L), which can be seen in some leukemic patients, is treated to prevent  leukostasis . [ 13 ] [ 14 ]


Leukopenia  (from  Greek     λευκός  (leukos)  'white' and    πενία  (penia)  'deficiency') is a decrease in the number of  leukocytes  ( WBC ). Found in the blood, they are the  white blood cells , and are the body's primary defense against an  infection . Thus the condition of leukopenia places individuals at increased risk of infection.


Symptoms may include:


Neutropenia , a subtype of leukopenia, refers to a decrease in the number of circulating  neutrophil granulocytes , the most abundant white blood cells. The terms  leukopenia  and  neutropenia  may occasionally be used interchangeably, as the neutrophil count is the most important indicator of infection risk.  Agranulocytosis  is an acute form of neutropenia. [ citation needed ]


Low white cell count may be due to acute viral infections, such as a cold or  influenza . It has been associated with  chemotherapy ,  radiation therapy ,  myelofibrosis ,  aplastic anemia  (failure of white cell, red cell and platelet production), stem cell transplant, bone marrow transplant,  HIV ,  AIDS , and steroid use. [ citation needed ]


Other causes of low white blood cell count include  systemic lupus erythematosus ,  Hodgkin's lymphoma , some types of  cancer ,  typhoid ,  malaria ,  tuberculosis ,  dengue ,  rickettsial infections , enlargement of the  spleen ,  folate  deficiencies,  psittacosis ,  sepsis ,  Sjögren syndrome  and  Lyme disease . It has also been shown to be caused by deficiency in certain  minerals , such as  copper  and  zinc . [ citation needed ]


Pseudoleukopenia can develop upon the onset of infection. The leukocytes (primarily neutrophils, responding to injury first) start migrating toward the site of infection, where they can be scanned. Their migration causes bone marrow to produce more WBCs to combat infection as well as to restore the leukocytes in circulation, but as the blood sample is taken upon the onset of infection, it contains low amount of WBCs, which is why it is termed "pseudoleukopenia". [ citation needed ]


Certain medications can alter the number and function of white blood cells. [ citation needed ]


Medications that can cause leukopenia include  clozapine , an  antipsychotic  medication with a rare adverse effect leading to the total absence of all granulocytes (neutrophils, basophils, eosinophils).  Minocycline , a commonly prescribed antibiotic, is another drug known to cause leukopenia. There are also reports of leukopenia caused by divalproex sodium or  valproic acid  (Depakote), a drug used for epilepsy (seizures), mania (with bipolar disorder) and migraine. [ citation needed ]


The  anticonvulsant  drug,  lamotrigine , has been associated with a decrease in white blood cell count. [ 2 ]


The FDA monograph for  metronidazole  states that this medication can also cause leukopenia, and the prescriber information suggests a complete blood count, including differential cell count, before and after, in particular, high-dose therapy. [ 3 ]


Immunosuppressive  drugs, such as  sirolimus ,  mycophenolate mofetil ,  tacrolimus ,  ciclosporin ,  leflunomide  and  TNF inhibitors , have leukopenia as a known complication. [ 4 ]   Interferons  used to treat  multiple sclerosis , such as  interferon beta-1a  and  interferon beta-1b , can also cause leukopenia. [ citation needed ]


Chemotherapy  targets cells that grow rapidly, such as tumors, but can also affect white blood cells, because they are characterized by bone marrow as rapid growing. [ 5 ]  A common side effect of cancer treatment is  neutropenia , the lowering of  neutrophils  (a specific type of white blood cell). [ 6 ]


Decreased white blood cell count may be present in cases of  arsenic toxicity . [ 7 ]


Leukopenia can be identified with a  complete blood count . [ 8 ]


Below are  blood reference ranges  for various types leucocytes/WBCs. [ 9 ]  The 2.5 percentile (right limits in intervals in image, showing 95%  prediction intervals ) is a common limit for defining  leukocytosis .


peripheral:   Purine nucleoside phosphorylase deficiency


Leukostasis  (also called symptomatic hyperleukocytosis) is a medical emergency most commonly seen in patients with  acute myeloid leukemia . It is characterized by an extremely elevated  blast cell  count and symptoms of decreased  tissue perfusion . The pathophysiology of leukostasis is not well understood, but inadequate delivery of oxygen to the body's cells is the result. Leukostasis is diagnosed when white cell plugs are seen in the  microvasculature . The most common symptoms are  dyspnea  and  hypoxia , usually accompanied by visual changes, headaches, dizziness, confusion, somnolence, and coma. Prompt treatment is required since, if left untreated, it has a very high mortality rate. Treatments aim to rapidly reduce white blood cell counts while also treating the underlying disorder.


Symptomatic Hyperleukocytosis (Leukostasis) is defined by a tremendously high  blast cell  count along with symptoms of decreased tissue  perfusion . Leukostasis is associated with people who have bone and blood disorders and is very common among people with  acute myeloid leukemia  or  chronic myeloid leukemia . Leukostasis is a pathologic diagnosis that inhibits efficient flow to the  microvasculature  of the body. Continued and untreated leukostasis presents  respiratory  and  neurological  distress simultaneously and is a medical emergency, with untreated patient mortality rates reaching a minimum of 20 and a maximum of 40 percent. A leukemia blood cell count greater than 50 x 10^9/ L (50,000 / microL) or 100 x 10^9 L / (100,000/ microL) signifies hyperleukocytosis. Symptoms of leukostasis start when blood levels of leukocytes reach over 100 x 10^9 / L (100,000 / microL). As stated before, these counts are critical and associated with  Leukemias . [ 1 ]


When a patient has symptomatic leukocytosis, specifically caused by a form of leukemia, it is common to find leukostasis in all their organs. The majority of the time a patient dies from neurological complications (40% of patients die due to neurological conditions) as opposed to particular organ damage. The lungs alone account for approximately 30 percent of leukostasis fatalities. All other organs combined attribute to 30 percent of deaths, with the major outliers being neurological and  respiratory failure  equating to 70 percent of all death rates. Damage to the  microvasculature  of the body is the primary cause of death by leukostasis. Microvasculature damage to the lungs is only second to neurological damage because the body is already experiencing hypoxic conditions, which lead to lung tissue damage as the second leading cause of fatalities. [ 2 ]


Pulmonary signs  -  Dyspnea  and  hypoxia  with or without diffuse interstitial or alveolar infiltrates on imaging studies.


Neurological signs  - visual changes, headaches, dizziness,  tinnitus , gait instability, confusion,  somnolence , coma.


The most common symptom is the patient is usually  febrile , which is often linked with inflammation and possible infection.


Less common signs include:  myocardial ischemia  / right  ventricular  overload, increased  acute kidney injury ,  priapism , acute limb  ischemia  and bowel  infarction .


Hyperleukocytosis is very common in acutely ill patients. It occurs in response to a wide variety of conditions, including  viral ,  bacterial ,  fungal , or  parasitic infection , cancer, hemorrhage, and exposure to certain medications.


For lung diseases such as  pneumonia  and  tuberculosis , white blood cell count is crucial for the diagnosis of the disease, as leukocytosis is usually present.


Specific medications, including  corticosteroids ,  lithium  and  beta-agonists  can cause hyperleukocytosis. [ 4 ]


The mechanism in which hyperleukocytosis or leukostasis manifests and disrupts  homeostasis  is greatly associated with leukemia's but multiple other factors may cause leukocytosis. Major types of leukocytosis and their mechanisms depend on the types of leukemia that cause them.  White blood cell  levels either rise in distinct white blood levels or in unison with others, a patient may have  neutrophilia ,  lymphocytosis ,  monocytosis ,  eosinophilia ,  basophilia  or a rise in immature  blast cells . [ 2 ]


Acute myeloid leukemia  - 10 to 20 percent of patients newly diagnosed with this type leukemia have hyperleukocytosis.


Acute lymphoblastic leukemia  - 20 to 30 percent of patients newly diagnosed with this type of leukemia have hyperleukocytosis.


Chronic lymphocytic leukemia  - Exact percentage of people diagnosed with chronic  lymphocytic  leukemia is unknown but a significant number also have hyperleukocytosis.


Chronic myeloid leukemia  - The majority of patients with chronic myeloid leukemia usually have hyperleukocytosis.


The primary pathophysiology of leukostasis is not completely understood, but there are two possible theories.


Increased blood viscosity due to large leukemic blast populations which are less deformable than mature leukocytes may lead to leukostasis. The accumulation of less malleable blast products in the bloodstream accumulate within the microcirculation causing an accumulation of blockages leading to leukostasis. [ citation needed ]


Hypoxic events in body regions may increase the high metabolic activity of dividing  blast cells  and lead to an increase in  cytokine  production. The increasing levels of  cytokines  within tissues may result in endothelial damage and subsequent  hemorrhage . Therefore, hypoxia, in addition to various cytokine accumulations, act in unison to further damage tissue and attract leukemic blast cells to form a triad of damage. [ citation needed ]


The combination of these theories, in addition to other events, may lead to hyperleukocytosis.


White blood counts exceeding 100 x 10^9 / L (100,000 / microL) present symptoms of tissue hypoxia and may signal possible neurological and respiratory distress. Ongoing research has shown that patients have experienced hypoxia at leukocyte levels below 100 x 10^9 / L (100,000 / microL), therefore patients with leukemia need regular neurological and respiratory monitoring when leukocyte counts are approaching 100 x 10^9 / L (100,000 / microL) to decrease chances of tissue hypoxia.


Acquired  biopsies  are examined for damage to microvasculature, which serves as evidence of hypoxia through the identification of leukocyte blockage within the tissue. Due to the  biopsy 's invasive nature and the risks associated with the procedure, it is only used when deemed necessary. [ 2 ]


Measurements for arterial pO2 have shown to be falsely decreased in patients with hyperleukocytosis because of white blood cells ability to utilize oxygen.  Pulse oximetry  should be used to more accurately assess  pO2  levels of a patient suspected to have leukocytosis. Automated blood cell counters may be inaccurate due to fragments of  blast cells  being labeled on  blood smears  as  platelets . The most accurate form of confirming platelet counts is by using a manual platelet count and a review of a peripheral smear. Serum potassium levels may also be artificially elevated by a release from leukemic blasts during  in vitro  clotting process, therefore serum potassium levels should be monitored by  heparinized  (the addition of  heparin  prevents  coagulation ) plasma samples in order to obtain accurate results of potassium levels.  Disseminated intravascular coagulation  may occur in a significant number of patients with presentation of various degrees of  thrombin  generation, followed by decreased fibrinogen and increased fibrinolysis. [ citation needed ]


Spontaneous  tumor lysis syndrome  is present in approximately 10 percent of patients with leukostasis. Lab tests are used to measure the potential of elevated serum concentrations such as  uric acid ,  potassium ,  phosphate , and  hypocalcemia .


Disseminated intravascular coagulation  and spontaneous  tumor lysis syndrome  can develop before and after chemotherapy treatment. Patients undergoing this type of therapy need to be closely monitored before and after, in addition to undergoing prophylactic measures to prevent possible complications.


Since leukostasis and hyperleukostasis are associated with leukemia, preventive treatments are taken upon diagnosis. [ 2 ]


Patients with hyperleukocytosis associated with leukemia are always considered candidates for tumor lysis syndrome prophylaxis in addition to aggressive intravenous hydration with allopurinol or  rasburicase  to decrease serum uric acid levels.


Treatment includes utilization of  prophylactic  methods if the patient has been diagnosed with hyperleukocytosis. This is usually in combination with other treatments, which are dependent on the type of leukemia. Specific treatments include lysis syndrome treatment in addition to aggressive  intravenous  hydration with  allopurinol  or  rasburicase  to decrease serum uric acid levels. [ 2 ]


Hematopoietic  cell transplants are critical to correct leukostasis and leukemia.  Cytoreduction  is also a critical course of treatment in order to rapidly decrease white blood cell counts. Twenty to forty percent of patients diagnosed with hyperleukocytosis die within the first week of symptom presentation. Patients with the best outcome have none or limited symptoms of respiratory or neurological distress. An accumulation of these symptoms lead to decreased levels of statistical survival compared to patients diagnosed with asymptomatic hyperleukocytosis alone. Cytoreduction methods include chemotherapy, utilizing the drug  hydroxyurea  (Hydroxyurea is usually used in asymptomatic hyperleukocytosis), and the less common  leukapheresis  procedure. This procedure is often utilized for asymptomatic hyperleukocytosis patients who have induction chemotherapy postponed for patient-specific factors. [ citation needed ]


Variants of  chemotherapy , including  induction chemotherapy , are used to treat both elevated white blood cells counts while simultaneously targeting  leukemia  cells in the  bone marrow . [ citation needed ]


Prognosis of patients with hyperleukocytosis is dependent on the cause and type of leukemia the patient has. Patients diagnosed with asymptomatic hyperleukocytosis have significantly better survival rates than symptomatic hyperleukocytosis (leukostasis). Preventative measures and contentious monitoring of patients diagnosed with leukemia is critical in receiving treatment as early as possible to prevent and treat hyperleukocytosis. [ citation needed ]


Recent and continuing research has shown that patients have had hypoxia at leukocyte levels below 100 x 10^9 / L (100,000 / microL), therefore patients with leukemia need regular neurological and respiratory monitoring when leukocyte counts are approaching 100 x 10^9 / L (100,000 / microL) to decrease chances of hypoxia. [ 2 ]


Leukemia and population types are also believed to be associated with possible symptoms and may require a change in treatment. [ 2 ]


Results of Tumor lysis/ consumption of coagulopathy in patients with acute leukemia is much more often than in patients with chronic malignant hematological diseases. [ 5 ]


Leukostasis , also known as  symptomatic hyperleukocytosis , is a life-threatening complication of various  leukemias  characterized by an  excess  of  white blood cells  in the bloodstream. Hyperleukocytosis is arbitrarily defined as greater than 100,000 white blood cells per microliter of blood. The condition is characterized by abnormal aggregation and clumping of white blood cells in the blood vessels resulting in impaired blood flow and delivery of oxygen to the body's cells. The  brain  and  lungs  are the two most commonly affected organs. [ 6 ]  Leukostasis most commonly occurs with  acute myeloid leukemia .


Hyperleukocytosis/leukostasis occurs more commonly, and at lower white blood cell (WBC) counts, in acute myeloid leukemia than in  acute lymphocytic leukemia , because the cells of acute myeloid leukemia have a larger corpuscular (cell) volume than those of acute lymphocytic leukemia, and the cells of acute myeloid leukemia have more surface adhesion molecules than those of acute lymphocytic leukemia (i.e., the cancer cells in AML are "stickier").


Individuals affected by leukostasis may present with respiratory symptoms such as  cough ,  difficulty breathing ,  breathing too quickly , or  inadequate levels of oxygen in the blood  requiring support with a  mechanical ventilator . [ 6 ] [ 7 ]  Neurologic symptoms, such as  temporary confusion , blurry vision, dizziness,  ringing in the ears ,  ataxia , stupor,  sleepiness ,  headaches , and  coma , may be seen. Neurologic signs such as  seizures , focal neurologic deficits (e.g., weakness in one arm or leg),  swelling of the retina , retinal bleeding, and dilated blood vessels on  inspection of the back of the eye . [ 7 ]  Rare complications of leukostasis include  renal vein thrombosis ,  priapism , and acute ischemia of the leg. [ 6 ]


The pathophysiology of leukostasis is not well understood.  Inadequate delivery of oxygen to the body's cells  is thought to be the main abnormal result of leukostasis. [ 7 ]  Proposed mechanisms for this include increased blood viscosity due to the high number of white blood cells circulating in the blood and a higher proportion of cells with a greater  mean corpuscular volume  (larger cells) with decreased deformability occupying the blood vessels. [ 6 ]  However, certain studies have demonstrated that the blood viscosity of affected individuals is not increased due to a compensatory decrease in the number of  red blood cells  sometimes resulting in  anemia  and a decreased  hematocrit . [ 7 ]


The clinical signs and symptoms of leukostasis are non-specific but should be suspected in susceptible individuals with leukemia, a high white blood cell count (e.g., over 100,000), and new-onset neurologic or respiratory signs or symptoms.  Rales  may be heard when  listening to the lungs with a stethoscope . [ 6 ]


A  chest x-ray  can be normal in those with leukostasis or may demonstrate an alveolar pattern of infiltrates. [ 7 ]  Brain imaging with  computed tomography  (CT) or  magnetic resonance imaging  (MRI) is useful and can demonstrate areas of bleeding,  ischemic stroke , or masses. [ 7 ]


Laboratory abnormalities seen in those with leukostasis include a markedly elevated white blood cell count (hyperleukocytosis) and  electrolyte  abnormalities seen with  tumor lysis syndrome  such as  high concentrations of potassium ,  phosphorus , and  uric acid  in the blood and a low level of  calcium  in the blood (due to being bound by high amounts of circulating phosphorus). [ 7 ]


It is an  acute  syndrome requiring aggressive  cytoreductive   modalities  including  chemotherapy  and/or  leukapheresis  to both reduce the number of circulating leukocytes and to break apart any aggregates that have already formed. Such rapid and massive  lysis  of tissue poses a risk of  complications  ( tumor lysis syndrome ), but it is necessary to avoid a  stroke .


Leukostasis is different from leukemic infiltration, which is a  neoplastic  process where leukemic cells invade organs. [ 8 ]


Leukostasis is a high-risk condition and can lead to significant complications resulting from occlusion of blood vessels, including  transient ischemic attacks  and  strokes .


The incidence and prevalence of hyperleukocytosis and leukostasis vary depending on the form of leukemia. [ 7 ]  Hyperleukocytosis is common in  chronic myelogenous leukemia  and  chronic lymphocytic leukemia , but leukostasis rarely occurs. [ 7 ]  Similarly, the incidence of hyperleukocytosis in people with  acute lymphoblastic leukemia  is between 10 and 30% but rarely does this progress to symptomatic leukostasis. [ 7 ]  The incidence of hyperleukocytosis in  acute myeloid leukemia  (AML) ranges between 5-20% but leukostasis is less common than hyperleukocytosis in this population; leukostasis tends to occur more often in people with AML with monocytic features. [ 7 ]


Light chain deposition disease  ( LCDD ) is a rare blood cell disease which is characterized by deposition of fragments of infection-fighting  immunoglobulins ,  called  light chains  (LCs), in the body. LCs are normally  cleared  by the kidneys, but in LCDD, these light chain deposits damage organs and cause disease. The kidneys are almost always affected and this often leads to kidney failure.  About half of people with light chain deposition disease also have a  plasma cell dyscrasia , a spectrum of diseases that includes  multiple myeloma ,  Waldenström's macroglobulinemia , and the  monoclonal gammopathy of undetermined significance   premalignant  stages of these two diseases. [ 1 ] [ 2 ]   Unlike in  AL amyloidosis , in which light chains are laid down in characteristic  amyloid  deposits, in LCDD, light chains are deposited in non-amyloid granules. [ 3 ]


Light chain  deposition disease can affect any organ. [ 3 ]  Renal involvement is always present and can be identified by microscopic  hematuria  and  proteinuria . Due to the gradual buildup of light chains from plasma filtration, renal function rapidly declines in the majority of patients with LCDD as either acute  tubulointerstitial nephritis  or rapidly progressing  glomerulonephritis . This condition can include  nephrotic syndrome ,  proteinuria , and/or  renal failure . [ 4 ]  Regardless of the degree of light chain excretion,  renal failure  happens with a comparable frequency. Furthermore,  hypertension  may be present at the time of diagnosis in patients with LCDD. [ 5 ]  Deposits may form in the skin,  lungs ,  gastrointestinal tract ,  thyroid glands ,  pancreas ,  bone marrow ,  spleen ,  lymph nodes , and  adrenal glands . [ 3 ]  Extrarenal deposition with symptoms is uncommon. It is unclear if localized LCDD is a real condition or if it is the first sign of a silent systemic LCDD. [ 6 ]


The  liver  is the most common extra-renal site in LCDD, although involvement is not always limited to this organ. There appears to be no relationship between the degree of light chain deposition within the liver and the severity of liver dysfunction. [ 7 ]  In addition to  portal hypertension  and  hepatic insufficiency , affected patients may die from  hepatic failure . [ 8 ]


Cardiac involvement may be linked to  paroxysmal atrial fibrillation , [ 9 ]  severe  congestive heart failure , and  restrictive cardiomyopathy . [ 10 ]


The lungs are rarely affected by light chain deposition disease, which typically damages the  parenchyma ; [ 11 ]  bronchial involvement seems to be extremely uncommon. [ 12 ]  However recent reports have indicated that the major airways are involved. There have been descriptions of nodular as well as diffuse pulmonary interstitial diseases; however, the literature has only reported seven occurrences of pulmonary nodular-type LCDD to date. [ 13 ]


The effects of systemic protein deposition on the nerves are comparable to those of  amyloidosis , which is clinically characterized by  polyneuropathy . [ 14 ]  Deposits may form in the  choroid plexus  and along  nerve fibers . [ 15 ]  Additionally, isolated LCDD within the brain has been reported. [ 16 ]


LCDD develops as a result of overproduction and thus deposition of abnormal  immunoglobulins . About 60% of cases develop in the context of  plasmacytoma ,  multiple myeloma , and other  lymphoproliferative disorders . However, in many cases, an underlying cause cannot be identified. [ 4 ]


The main  light chain  structure in LCDD presumably dictates how the disease manifests in the body. Though κI-IV has been described, [ 17 ]  the sequenced kappa light chains in LCDD are more likely to belong to the V-region subtype, of which VκIV appears to be overrepresented. [ 18 ]  The pathogenicity of these proteins has not been linked to any particular structural pattern or residue, but a number of recurring characteristics have been identified. [ 19 ]  Firstly,  somatic mutations , not  germline mutations , are the source of the  amino acid substitutions . Secondly, the region that determines complementarity is where substitutions happen most frequently. [ 17 ]  Third,  hydrophobic residues  are more likely to be introduced by the mutations reported in both the kappa and  light chains . [ 20 ]  This could disrupt protein-protein interactions and destabilize the protein, leading to protein deposition in tissues. [ 21 ]  The propensity for aggregation is exemplified in a  murine  model of LCDD where light chain deposition was observed in the kidney of transfected mice using vectors that contained kappa light chain sequence from an individual with LCDD with the VκIV subtype. [ 22 ]  Lastly, because some patients with LCDD have isolates of kappa light chains with mutations that produce new  N-glycosylation  sites, posttranslational modification can be linked to the creation of pathologic light chains. [ 23 ]  It is possible that the new  hydrophobic residues  along with  N-glycosylation  sites will make it more likely for the light chains to accumulate in the affected tissues'  basement membranes . [ 24 ]  The  mesangial cell  is also thought to play a role in the pathogenesis of LCDD. [ 25 ]


A number of laboratory tests are required in order to assist in diagnosing LCDD. Blood and urine samples are collected for evaluation of kidney and liver function and determination of the presence of a monoclonal protein. Imaging studies such as  echocardiography  and an  ultrasound  of the abdomen will be performed. A  CT scan ,  magnetic resonance imaging (MRI)  or  positron emission tomography  (PET) may also be indicated. [ 26 ]


Patients suspected of having LCDD should be evaluated using the screening panel for plasma cell proliferative disorders. [ 27 ]  However, the sensitivity of laboratory testing strategies for detecting  monoclonal gammopathies  has increased with the development of quantitative serum assays to test for  immunoglobulin free light chain ; [ 28 ]  this increased diagnostic sensitivity is easily noticeable in the  monoclonal light chain  diseases. [ 29 ]  The most recent diagnostic screening guidelines state that serum  immunofixation  in addition to  immunoglobulin free light chain  is an adequate screening panel for plasma cell proliferative disorders apart from  AL amyloidosis  and LCDD due to the increased sensitivity for free light chain diseases. It is advised, nevertheless, that urine  immunofixation  be used in addition to LCDD and  AL amyloidosis  screening. [ 27 ]


The  immunohistologic  examination of tissue from an afflicted organ—which is not congophilic in nature—confirms the diagnosis of LCDD. The tissue's light chain restriction evaluation will determine whether the heavy or light chain is  monoclonal . An  abdominal ultrasound  and  echocardiography  should be part of the workup when an individual is diagnosed with LCDD in order to evaluate the  spleen ,  liver , and  lymph nodes . A  bone marrow aspirate  as well as biopsy are necessary to rule out  light amyloidosis  and/or  multiple myeloma . [ 5 ]


Similar to  cardiac amyloid ,  diastolic dysfunction  and a decrease in myocardial compliance may be discovered via  echocardiography  and  catheterization . [ 30 ]


By using specific  light chain  stains in  glomeruli  as well as negative  Congo red stain , tubular  basement membranes , and punctate amorphous, ground-pepper-like appearance of deposits on  electron microscopy , LCDD can be differentiated from other causes of  nodular sclerosis  and mesangial expansion.  Diabetic nephropathy  exhibits no deposits; fibrillary  glomerulonephritis  is  Congo red  negative and has a proliferative appearance along with polyclonal  immunoglobulin G ; other  monoclonal immunoglobulin deposition disease  exhibit both light and  heavy chain  staining or just heavy chain staining. Additional reasons for a  membranoproliferative glomerulonephritis  pattern exhibit  electron microscopy  appearances and  immunofluorescence  specific to the disease. [ 31 ]


Decreasing production of the organ-damaging light chains is the treatment goal. Options include chemotherapy using  bortezomib ,  autologous stem cell transplantation ,  immunomodulatory drugs , and  kidney transplant . [ 32 ]  There is no standard treatment for LCDD. High-dose  melphalan  in conjunction with autologous stem cell transplantation has been used in some patients. A regimen of  bortezomib  and  dexamethasone  has also been examined. [ 1 ]


Different  light chain  deposition does not appear to have an impact on the clinical course of LCDD patients, as the clinical presentation is known to depend on the quantity and type of affected organs. [ 33 ]  The median survival time is roughly four years. Following a median follow-up of 27 months, the most comprehensive series to date found that 59% of cases resulted in death and 57% of cases reached  uremia . [ 4 ]  LCDD prognostic factors include age, extrarenal light chain deposition, and  plasma cell myeloma . [ 34 ]


Being a relatively rare condition, LCDD is commonly misdiagnosed as a protein disease. Up to 50% of patients receive an LCDD diagnosis as a result of  lymphoproliferative disorders  such as  multiple myeloma . [ 35 ]  LCDD is diagnosed at a median age of 58 years. [ 4 ]  LCDD affects men 2.5 times more than women [ 8 ]  and is frequently linked with  monoclonal gammopathies of unknown significance  in 17% of patients. [ 5 ]


Macroamylasemia  is the presence of macroamylase in the blood. Macroamylase is a complex of the enzyme  amylase  bound to other proteins forming a larger  molecule . [ 1 ]  Macroamylase is typically composed of  immunoglobulin A  (IgA, 70%) and less often of  immunoglobulin G  (IgG, 30%). The association of amylase with some drugs has also been reported.
 [ 2 ]


The macroamylase molecules are unable to pass through the  kidneys  and are therefore retained in the blood, leading to elevated levels of  amylase  in the  bloodstream . In contrast, amylase urine levels are normal. [ 3 ]


Macroamylasemia is usually a benign condition, and people usually do not experience any symptoms or health problems. In fact, it is often discovered incidentally during a routine blood test. However, in some rare cases, macroamylasemia can cause recurrent  abdominal pain  or other gastrointestinal symptoms.


Macroamylasemia is a relatively rare condition, and in most cases, the exact cause is unknown. It can occur in completely healthy individuals without symptoms, in association with autoimmune diseases (such as  systemic lupus erythematosus ) and other diseases (cancer or inflammatory diseases). [ 2 ]


However, there are some risk factors that can increase the likelihood of developing the condition: [ 4 ]


Diagnosis of macroamylasemia is typically made by measuring the  amylase  levels in the blood and urine and performing additional tests to confirm the presence of macroamylase. [ 5 ]


Treatment is usually not necessary unless the patient is experiencing symptoms or complications related to the condition. [ citation needed ]


Macroglobulinemia  is the presence of increased levels of  macroglobulins  in the circulating  blood .
It is a  plasma cell dyscrasia , resembling  leukemia , with cells of lymphocytic, plasmacytic, or intermediate morphology, which secrete a monoclonal  immunoglobulin M  component. There is diffuse infiltration by the malignant cells of the bone marrow and also, in many cases, of the spleen, liver, or lymph nodes. The circulating macroglobulin can produce symptoms of hyperviscosity syndrome: weakness, fatigue, bleeding disorders, and visual disturbances. Peak incidence of macroglobulinemia is in the sixth and seventh decades of life. (Dorland, 28th ed)


Methaemalbuminaemia  is a clinical condition that can be caused by severe  intravascular   haemolysis  or acute  haemorrhagic   pancreatitis . This can be due to  proteolytic  breakdown of  haemoglobin  to form both  haem  and methaem. Methaem combines with  blood plasma   albumin  to form  methemalbumin  which is found in trace amount in the blood.
Bleeding into the  abdominal cavity  is another known cause of methaemalbuminaemia.
Methaemalbumin in blood is detected by carrying out a test known as  Schumm test  which is a  spectroscopic  identification on addition of  ammonium sulphide .


Neutropenia  is an abnormally low concentration of  neutrophils  (a type of  white blood cell ) in the blood. [ 4 ]  Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against  infections  by destroying  bacteria , bacterial fragments and  immunoglobulin -bound  viruses  in the  blood . [ 5 ]  People with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening ( neutropenic sepsis ). [ 6 ]


Neutropenia can be divided into congenital and acquired, with  severe congenital neutropenia  (SCN) and  cyclic neutropenia  (CyN) being autosomal dominant and mostly caused by heterozygous mutations in the ELANE gene ( neutrophil elastase ). [ 7 ]  Neutropenia can be  acute  (temporary) or  chronic  (long lasting). The term is sometimes used interchangeably with " leukopenia " ("deficit in the number of white blood cells"). [ 8 ]


Decreased production of neutrophils is associated with deficiencies of  vitamin B12  and  folic acid ,  aplastic anemia ,  tumors , drugs, metabolic disease, nutritional deficiencies (including minerals such as copper), and immune mechanisms. In general, the most common oral manifestations of neutropenia include ulcer,  gingivitis , and periodontitis.  Agranulocytosis  can be presented as whitish or greyish necrotic ulcer in the oral cavity, without any sign of inflammation. Acquired agranulocytosis is much more common than the congenital form. The common causes of acquired agranulocytosis including drugs (non-steroidal anti-inflammatory drugs, antiepileptics, antithyroid, and antibiotics) and viral infection. Agranulocytosis has a mortality rate of 7–10%. To manage this, the application of granulocyte colony stimulating factor (G-CSF) or  granulocyte transfusion  and the use of broad-spectrum antibiotics to protect against bacterial infections are recommended. [ 9 ]


Signs and symptoms of neutropenia include  fever ,  painful swallowing ,  gingival  pain, skin  abscesses , and  otitis . These symptoms may exist because individuals with neutropenia often have  infection . [ 3 ]


Children may show signs of  irritability  and  poor feeding . [ 10 ]   Hypotension  has also been observed in individuals with this condition. [ 6 ]


The causes of neutropenia can be divided between problems that are  transient  and those that are  chronic . Causes can be divided into these groups: [ 1 ] [ 2 ] [ 11 ] [ 12 ]


Severe bacterial infections, especially in people with underlying hematological diseases or  alcoholism , can deplete neutrophil reserves and lead to neutropenia. [ 2 ]   Gram-positive bacteria  are present in 60–70% of bacterial infections. There are serious concerns regarding  antibiotic-resistant  organisms. These would include as methicillin-resistant  Staphylococcus aureus  ( MRSA ) or vancomycin-resistant Enterococcus ( VRE ). [ 31 ]


Nutritional deficiencies, such as deficiency in  vitamin B12 ,  folate ,  copper  or  protein-calorie malnutrition  are associated with chronic neutropenia. However, nutritional deficiencies are usually associated with decreases in other cell lines (multiple cytopenia or pancytopenia) rather than isolated neutropenia. [ 2 ]


Other causes of congenital neutropenia are  Shwachman–Diamond syndrome , Cyclic neutropenia,  bone marrow  failure syndromes, cartilage–hair hypoplasia, reticular dysgenesis, and  Barth syndrome . Viruses that infect neutrophil progenitors can also be the cause of neutropenia. Viruses identified that have an effect on neutrophils are rubella and cytomegalovirus. [ 1 ]  Though the body can manufacture a normal level of neutrophils, in some cases the destruction of excessive numbers of neutrophils can lead to neutropenia. These are: [ 1 ]


The  pathophysiology  of neutropenia can be divided into  congenital  and  acquired . The  congenital  neutropenia (severe and  cyclic  type) is  autosomal dominant , with mutations in the  ELA2  gene ( neutrophil elastase ) as the most common genetic reason for this condition. [ 7 ]  Acquired neutropenia (immune-associated neutropenia) is due to anti-neutrophil  antibodies  that target neutrophil-specific  antigens , ultimately altering neutrophil function. [ 32 ]  Furthermore, emerging research suggests neutropenia without an identifiable etiology (idiopathic neutropenia) may be the result of a  low-grade, chronic inflammatory process with an abnormal excessive production of myelosuppressive cytokines in a study conducted in the island of Crete. [ 33 ]


Neutropenia fever can complicate the treatment of  cancers . Observations of  children  noted that  fungal  infections are more likely to develop in those with neutropenia. Mortality increases during cancer treatments if neutropenia is also present. [ 6 ]
Congenital neutropenia is determined by blood neutrophil counts (absolute neutrophil counts or ANC) < 0.5 × 10 9 /L and recurrent bacterial infections beginning very early in childhood. [ 34 ]  Congenital neutropenia is related to  alloimmunization , sepsis, maternal  hypertension ,  twin-to-twin transfusion syndrome , and  Rh hemolytic disease . [ 1 ]


Neutropenia can be the result of a variety of consequences, including taking certain types of drugs, exposure to environmental toxins, vitamin deficiencies, metabolic abnormalities, as well as cancer, viral or bacterial infections. Neutropenia itself is a rare entity, but can be clinically common in oncology [ 35 ]  and immunocompromised individuals as a result of chemotherapy (drug-induced neutropenia). Additionally, acute neutropenia can be commonly seen from people recovering from a viral infection or in a post-viral state. Meanwhile, several subtypes of neutropenia exist which are rarer and chronic, including acquired (idiopathic) neutropenia, cyclic neutropenia, autoimmune neutropenia, and congenital neutropenia. [ 36 ] [ 37 ]


Neutropenia that is developed in response to chemotherapy typically becomes evident in seven to fourteen days after treatment, this period is known as the  nadir  or "low point". [ 38 ] [ 39 ]  Conditions that indicate the presence of neutropenic fever are implanted devices; leukemia induction; the compromise of mucosal, mucociliary and cutaneous barriers; a rapid decline in absolute neutrophil count, duration of neutropenia >7–10 days, and other illnesses that exist in the patient. [ 31 ]


Signs of infection can be subtle. Fevers are a common and early observation. Sometimes overlooked is the presence of  hypothermia , which can be present in sepsis. Physical examination and accessing the history and physical examination is focused on sites of infection. Indwelling line sites, areas of skin breakdown, sinuses, nasopharynx, bronchi and lungs, alimentary tract, and skin are assessed. [ 31 ]


The diagnosis of neutropenia is done via the low neutrophil count detection on a  complete blood count . Generally, other investigations are required to arrive at the right diagnosis. When the diagnosis is uncertain, or serious causes are suspected,  bone marrow biopsy  may be necessary. A bone marrow biopsy can identify abnormalities in myelopoesis contributing to neutropenia such as the stage of arrest in the development of myeloid progenitor cells. [ 2 ]  Bone marrow biopsies can also be used to monitor the development of  myelodysplastic syndrome  (MDS) or  acute myeloid leukemia  (AML) in patients with chronic neutropenia (especially in those with  severe congenital neutropenia  (SCN) which carries a higher risk of MDS and AML)). [ 2 ]  Other investigations commonly performed: serial neutrophil counts for suspected cyclic neutropenia, tests for  antineutrophil antibodies ,  autoantibody  screen (and investigations for  systemic lupus erythematosus ),  vitamin B 12  and  folate  assays. [ 40 ] [ 41 ]  Rectal examinations are usually not performed due to the increased risk of introducing bacteria into the blood stream and the possible development of rectal abscesses. [ 31 ]


Generally accepted  reference range  for  absolute neutrophil count  (ANC) in adults is  1500 to 8000 cells per microliter (μL) of blood . Three general guidelines are used to classify the severity of neutropenia based on the ANC (expressed below in cells/μL): [ 42 ]


Each of these are either derived from laboratory tests or via the formula below:


ANC =

 (
 %
 n
 e
 u
 t
 r
 o
 p
 h
 i
 l
 s
 +
 %
 b
 a
 n
 d
 s
 )
 ×
 (
 W
 B
 C
 )

 (
 100
 )

 {\displaystyle (\%neutrophils+\%bands)\times (WBC) \over (100)}

 [ 1 ] [ 42 ] [ 43 ]


A fever, when combined with profound neutropenia ( febrile neutropenia ), is considered a medical emergency and requires broad spectrum antibiotics. An absolute neutrophil count less than 200 is also considered a medical emergency and almost always requires hospital admission and initiation of broad spectrum antibiotics with selection of specific antibiotics based on local resistance patterns. [ 2 ] Precautions to avoid opportunistic infections in those with chronic neutropenia include maintaining proper soap and water hand hygiene, good dental hygiene and avoiding highly contaminated sources that may contain a large fungal reservoirs such as mulch, construction sites and bird or other animal waste. [ 2 ]


Neutropenia can be treated with the hematopoietic growth factor  granulocyte-colony stimulating factor  (G-CSF). These are cytokines that are present naturally in the body. The factors promote neutrophil recovery following anticancer therapy or in chronic neutropenia. [ 1 ]  Recombinant G-CSF factor preparations, such as  filgrastim [ 44 ]  can be effective in people with congenital forms of neutropenia including severe congenital neutropenia and cyclic neutropenia; [ 45 ]  the amount needed (dosage) to stabilize the neutrophil count varies considerably (depending on the individual's condition). [ 46 ]  Guidelines for neutropenia regarding diet are currently being studied. [ 47 ]  Those who have chronic neutropenia and fail to respond to G-CSF or who have an increased risk of developing MDS or AML (due to increased dosage requirements of G-CSF or having abnormal precursor cells in the bone marrow)  often require  hematopoietic stem cell transplantation  as a treatment. [ 2 ]


Most cases of neonatal neutropenia are temporary. Antibiotic prophylaxis is not recommended because of the possibility of encouraging the development of multidrug-resistant bacterial strains. [ 1 ]


These are cytokines that are present naturally in the body. The factors promote neutrophil recovery following anticancer therapy. [ 1 ]


The administration of intravenous immunoglobulins (IVIGs) has had some success in treating neutropenias of alloimmune and autoimmune origins with a response rate of about 50%. Blood transfusions have not been effective. [ 1 ]


Patients with neutropenia caused by cancer treatment can be given antifungal drugs. A Cochrane review  [ 48 ]  found that lipid formulations of amphotericin B had fewer side effects than conventional amphotericin B, though it is not clear whether there are particular advantages over conventional amphotericin B if given under optimal circumstances. Another Cochrane review  [ 49 ]  was not able to detect a difference in effect between amphotericin B and fluconazole because available trial data analysed results in a way that disfavoured amphotericin B.


Trilaciclib, a  CDK4/6 inhibitor , administered approximately thirty minutes before chemotherapy, has been shown in three clinical trials to significantly reduce the occurrence of chemotherapy-induced neutropenia and the associated need for interventions such as the administration of  G-CSF 's. [ 50 ]  The drug was approved in February 2021  by the FDA for use in patients with extensive-stage small cell lung cancer. [ 50 ]


In November 2023, FDA approved  efbemalenograstim alfa . [ 51 ]


If left untreated, people with fever and absolute neutrophil count <500 have a mortality of up to 70% within 24 hours. [ 31 ]  The prognosis of neutropenia depends on the cause.  Antibiotic  agents have improved the prognosis for individuals with severe neutropenia.  Neutropenic fever  in individuals treated for cancer has a mortality of 4–30%. [ 52 ]


Neutropenia is usually detected shortly after birth, affecting 6% to 8% of all newborns in  neonatal  intensive care units (NICUs). Out of the approximately 600,000 neonates annually treated in NICUs in the United States, 48,000 may be diagnosed as neutropenic. The incidence of neutropenia is greater in premature infants. Six to fifty-eight percent of preterm neonates are diagnosed with this auto-immune disease. The incidence of neutropenia correlates with decreasing birth weight. The disorder is seen up to 38% in infants that weigh less than 1000g, 13% in infants weighing less than 2500g, and 3% of term infants weighing more than 2500 g. Neutropenia is often temporary, affecting most newborns in only first few days after birth. In others, it becomes more severe and chronic indicating a deficiency in innate immunity. [ 1 ]


Furthermore, the prevalence of chronic neutropenia in the general public is rare. In a study conducted in Denmark, over 370,000 people were assessed for the presence of neutropenia. Results published demonstrated only 1% of those evaluated were neutropenic, and were commonly seen in those with HIV, viral infections, acute leukemias, and  myelodysplastic syndromes . The study concluded the presence of neutropenia is an ominous sign that warrants further investigation and follow-up. [ 53 ]


No reflow phenomenon  is the failure of blood to  reperfuse  an  ischemic  area after the physical obstruction has been removed or bypassed. The underlying mechanism is related to arterial microvasculature damage. It is primarily seen during  percutaneous coronary intervention (PCI)  in the setting of  acute myocardial infarction (AMI) , but has also been observed in other organs, including the brain and kidneys. [ 1 ]  Coronary no-reflow phenomenon is specifically related to reduced antegrade coronary blood flow despite proximal coronary artery patency. It is an independent predictor of worse clinical outcomes including heart failure, fatal arrhythmias, myocardial infarction, and increased mortality rates. [ 2 ]


The underlying mechanism of no reflow phenomenon is centered around the damage caused by microvascular obstruction (MVO). There have been two proposed underlying causes of no reflow phenomenon:


In both types of no reflow phenomenon, the extent of damage to the microvasculature is directly proportional to the length of time the tissue is ischemic, with longer periods of ischemia related to greater damage to the arterial microvasculature. [ 3 ]


Ornithinaemia  is a  blood disorder  characterized by high levels of  ornithine .  Also known as hyperornithinemia, it may be associated with  psychomotor retardation  or  epileptic  episodes. [ 1 ]


Pancytopenia  is a  medical condition  in which there is significant reduction in the number of almost all blood cells ( red blood cells ,  white blood cells ,  platelets ,  monocytes ,  lymphocytes , etc.).


If only two parameters from the  complete blood count  are low, the term  bicytopenia  can be used.  The diagnostic approach is the same as for pancytopenia.


Iatrogenic causes of pancytopenia include chemotherapy for malignancies if the drug or drugs used cause  bone marrow suppression . Rarely, drugs ( antibiotics , blood pressure medication, heart medication) can cause pancytopenia.
For example, the antibiotic  chloramphenicol  can cause pancytopenia in some individuals. [ 1 ]


Rarely, pancytopenia may have other causes, such as  mononucleosis  or other viral diseases. Increasingly,  HIV  is itself a cause of pancytopenia. [ 2 ]


The mechanism of pancytopenia involves either haemopoiesis itself, decreasing blood cell productions in number (aplastic anemia), haemopoietic stem cells are displaced by malignant cells (Leukemia, lymphoma, MDS) or they are being pooled (sequestrated) (spleen)/destroyed (immune) outside bone marrow. The mechanisms for pancytopenia differ according to the  etiology . For example, in  hemophagocytic lymphohistiocytosis  (HLH) there is marked inappropriate and ineffective  T cell  activation that leads to an increased hemophagocytic activity. The T cell activated  macrophages  engulf erythrocytes, leukocytes, platelets, as well as their  progenitor cells . Along with pancytopenia, HLH is characterized by  fever ,  splenomegaly , and hemophagocytosis in  bone marrow ,  liver , or  lymph nodes . [ 4 ]


Pancytopenia usually requires a  bone marrow biopsy  in order to distinguish among different causes. [ 5 ]


Treatment is done to address the underlying cause. To tide over immediate crisis  blood transfusion  with  packed red blood cells  (PRBC) or platelet transfusion may be done. Sometimes there are obvious clinical clues to suggest underlying B12 deficiency for a cause of  pancytopenia. [ 6 ]  In this selected cases even with severe anemia blood product transfusions can be avoided and vitamin B12 treatment itself suffice. [ 7 ]  In other situations like acute leukemia, Myelodysplastic syndrome, aplastic anemia etc. disease specific therapy is needed. [ 8 ]


Pseudothrombocytopenia  (PTCP) or  spurious thrombocytopenia  is an  in-vitro  sampling problem which may mislead the diagnosis towards the more critical condition of  thrombocytopenia . The phenomenon may occur when the  anticoagulant  used while testing the blood sample causes clumping of  platelets  which mimics a low platelet count. [ 1 ]
The phenomenon has first been reported in 1969. [ 2 ] [ 3 ]


EDTA-dependent agglutination


In some individuals, clinically insignificant antibodies may cause  in vitro  agglutination of platelets. As a result of platelet clumping, platelet counts reported by automated counters may be much lower than the actual count in the blood because these devices cannot differentiate platelet clumps from individual cells.
Pseudothrombocytopenia has been reported in association with the use of  EDTA  as an anticoagulant, with platelet cold agglutinins, and with  multiple myeloma . [ citation needed ]
Other risk factors associated with pseudothrombocytopenia are  autoimmune diseases ,  infections , pregnancy and the treatment with some medications such as  low-molecular-weight heparin ,  valproic acid ,  insulin ,  antibiotics  and chemotherapy medications like  sunitinib . [ 3 ]


The prevalence of pseudothrombocytopenia in K2-EDTA reported in different studies ranges from 0.03 to 0.27 percent in outpatients, [ 3 ]  which accounts for 15 to 30 percent of all cases of isolated thrombocytopenia.
Tests can mistake small clumps of platelets for leukocytes, thus showing a pseudo leukocytosis  in blood counts. [ 4 ]


Platelet satellitism


Platelet rosetting, or satelliting, around  white blood cells  can lead to undercounting by automated analyzers. [ 5 ]


Clotted samples


Coagulation within the sample leads to undercounting, because the analyzer samples the liquid part of the blood, while some of the platelets remain in the tube, trapped in the clot.  Overfilling the sample, or inadequately mixing with anticoagulant, may allow small clots to form.  Unlike platelet clumps, clots usually cannot be detected by reviewing the peripheral blood smear, but may be detected by probing with wooden sticks, including checking under the cap. [ 6 ]


A pseudothrombocytopenia false-positive result may occur when automated platelet counting devices are used. As a means of double checking the results, the patient's blood sample is often examined under a microscope.  If the clumping is visible and the number of platelets appears normal, pseudothrombocytopenia may be concluded. A second sample run with a different anticoagulant such as sodium citrate (blue top tube) to confirm the finding of pseudothrombocytopenia may be requested if there are doubts or concerns. [ 7 ]  Other alternative anticoagulants are  sodium fluoride , CPT ( trisodium citrate ,  pyridoxal 5′-phosphate  and  tris ), CTAD (citrate,  theophylline ,  adenosine , and  dipyridamole ),  magnesium sulfate  and  acid-citrate-dextrose . [ 3 ]


Rh disease  (also known as  rhesus  isoimmunization ,  Rh (D) disease , or  rhesus incompatibility , and blue baby disease) is a type of  hemolytic disease of the fetus and newborn  (HDFN).  HDFN due to anti-D antibodies is the proper and currently used name for this disease as the Rh blood group system actually has more than 50 antigens and not only the D-antigen. The term "Rh Disease" is commonly used to refer to HDFN due to anti-D antibodies, and prior to the discovery of anti-Rh o (D)  immune globulin, it was the most common type of HDFN. The disease ranges from mild to severe, and occurs in the second or subsequent pregnancies of  Rh-D negative  women when the biologic father is Rh-D positive.


Due to several advances in modern medicine, HDFN due to anti-D is preventable by treating the mother during pregnancy and soon after delivery with an  injection  of  anti-Rh o (D) immune globulin  (Rhoclone, Rhogam, AntiD).  With successful mitigation of this disease by prevention through the use of anti-Rh o (D)  immune globulin, other antibodies are more commonly the cause of HDFN today.


During pregnancy, there is normally a barrier between maternal and fetal blood called the placenta, a temporary organ that connects a mother’s uterus to the umbilical cord to provide nutrients and oxygen to the fetus. However, in certain circumstances, small amounts of fetal blood cells may enter the mother’s circulation. Certain types of events where this occurs are during childbirth, miscarriage or abortion, trauma, and invasive procedures such as amniocentesis. Once the fetal Rh-positive red blood cells enter the bloodstream of a Rh-negative mother, they are recognized as foreign. The mother’s immune system reacts to the Rh-positive red blood cells the same way that it would respond to something like a virus or bacteria, activating B cells — a type of white blood cell that is key to the triggering of an immune response. These activated B cells then differentiate into plasma cells, which produce anti-D antibodies. After the primary exposure, some of these B cells become memory cells, that remember the original exposure and produce IgG antibodies, which are smaller and can cross the placental barrier. Once they cross this barrier, they are into the fetal bloodstream, binding to fetal Rh-positive cells, triggering opsonization, which marks the red blood cells for destruction. The fetal spleen and liver then begin to break down those red blood cells, thinking that they are a foreign invader when in reality they are they are just mismatched. [ 1 ]


Symptoms of Rh disease include yellowish amniotic fluid and enlarged spleen, liver or heart or buildup of fluid in the abdomen of the fetus. [ 2 ]


During the first pregnancy, the Rh- mother's initial exposure to fetal Rh+ red blood cells (RBCs) is usually not sufficient to activate her Rh-recognizing B cells. However, during delivery, the placenta separates from the uterine wall, causing umbilical cord blood to enter the maternal circulation, which results in the mother's proliferation of IgM-secreting plasma B cells to eliminate the fetal Rh+ cells from her blood stream.  IgM   antibodies  do not cross the  placental barrier , which is why no effects to the fetus are seen in first pregnancies for Rh-D mediated disease. However, in subsequent pregnancies with Rh+ fetuses, the IgG memory B cells mount an immune response when re-exposed, and these  IgG  anti-Rh(D) antibodies  do  cross the placenta and enter  fetal circulation . These antibodies are directed against the  Rhesus (Rh) factor , a protein found on the surface of the fetal RBCs. The antibody-coated RBCs are destroyed by IgG antibodies binding and activating complement pathways. [ 4 ]


The resulting anemia has multiple sequelae: [ 5 ] [ 6 ] [ 7 ]


The destruction of RBCs leads to elevated bilirubin levels ( hyperbilirubinemia ) as a byproduct. This is not generally a problem during pregnancy, as the maternal circulation can compensate. However, once the infant is delivered, the immature system is not able to handle this amount of bilirubin alone and  jaundice  or  kernicterus  (bilirubin deposition in the brain) can develop which may lead to brain damage or death. Sensitizing events during pregnancy include  c-section ,  miscarriage ,  therapeutic abortion ,  amniocentesis ,  ectopic pregnancy , abdominal trauma and  external cephalic version . However, in many cases there was no apparent sensitizing event. Approximately 50% of Rh-D positive infants with circulating anti-D are either unaffected or only mildly affected requiring no treatment at all and only monitoring. An additional 20% are severely affected and require transfusions while still in the uterus. This pattern is similar to other types of HDFN due to other commonly encountered antibodies (anti-c, anti-K, and Fy(a)). [ citation needed ]


In the United States, it is a standard of care to test all expecting mothers for the presence or absence of the RhD protein on their RBCs. However, when medical care is unavailable or prenatal care not given for any other reason, the window to prevent the disease may be missed. In addition, there is more widespread use of molecular techniques to avoid missing women who appear to be Rh-D positive but are actually missing portions of the protein or have hybrid genes creating altered expression of the protein and still at risk of HDFN due to Anti-D. [ 8 ] [ 9 ]


Blood is generally drawn from the biological father to help determine fetal antigen status. [ 11 ]  If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDFN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. [ 12 ]


The protection that is offered today against Rh incompatibility involved preventive measures that primarily utilize Rh immunoglobulin, also known as RhoGAM. [ 13 ]  The aim of these treatments are to prevent the mother’s immune system from becoming sensitized to the Rh antigen, which reduces the risk of hemolytic disease in future pregnancies. RhoGAM, Rh Immunoglobulin Administration, is a product that contains antibodies to the Rh D antigen, it is used to prevent the mother from developing an immune response to fetal red blood cells. RhIg ‘coats’ any Rh-positive fetal red blood cells that enter the mother’s bloodstream, effectively ‘hiding’ them from the mother’s immune system. RhoGAM is typically administered at around 28 weeks of pregnancy, then again within 72 hours after childbirth. It is also given during other events that happen during pregnancy like miscarriages, ectopic pregnancies, amniocentesis, and abdominal trauma  [ 14 ]


In Arar, Saudi Arabia, results of a study showed that women had a low level of knowledge regarding maternal-fetal blood incompatibility (about 38% of the studied mothers during the research, had knowledge about Rh incompatibility). Regarding their knowledge about anti-D, researchers found that; 68.5% of the mothers had knowledge about it, while only 51% of the mothers had knowledge about the administration of prophylactic anti D after delivery. [ 15 ]


As medical management advances in this field, it is important that these patients be followed by high risk obstetricians/maternal-fetal medicine, and skilled neonatologists postpartum to ensure the most up to date and appropriate standard of care [ citation needed ]


In 1939 Drs.  Philip Levine  and  Rufus E. Stetson  published their findings about a 25-year-old mother who had a  stillborn  baby that died of  hemolytic disease of the newborn . [ 19 ]  Both parents were  blood group  O, so the husband's blood was used to give his wife a  blood transfusion  due to blood loss during delivery. However, she had a severe  transfusion reaction . Since both parents were blood group O, which was believed to be compatible for transfusion, they concluded that there must be a previously undiscovered blood group  antigen  that was present on the husband's red blood cells (RBCs) but not present on his wife's. This suggested for the first time that a mother could make blood group antibodies because of immune sensitization to her  fetus 's RBCs as her only previous exposure would be the earlier pregnancy. They did not name this blood group antigen at the time, which is why the discovery of the  rhesus  blood type is credited to Drs.  Karl Landsteiner  and  Alexander S. Wiener [ 20 ]  with their first publication of  their tables  for  blood-typing  and cross-matching in 1940, which was the culmination of years of work. However, there were multiple participants in this scientific race and almost simultaneous publications on this topic. Levine published his theory that the disease known as erythroblastosis fetalis was due to Rh alloimmunization in 1941 while Landsteiner and Wiener published their method to type patients for an antibody causing transfusion reactions, known as “Rh". [ 21 ] [ 22 ] [ 23 ]


The first treatment for Rh disease was an  exchange transfusion  invented by Wiener [ 24 ]  and later refined by Dr. Harry Wallerstein. [ 25 ]  Approximately 50,000 infants received this treatment. However, this could only treat the disease after it took root and did not do anything to prevent the disease. In 1960,  Ronald Finn , in  Liverpool , England proposed that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells (anti-RhD). [ 26 ]  Nearly simultaneously, Dr. William Pollack, [ 27 ]  an immunologist and protein chemist at  Ortho Pharmaceutical Corporation , and Dr. John Gorman (blood bank director at Columbia-Presbyterian) with Dr. Vincent Freda (an obstetrician at  Columbia-Presbyterian Medical Center ), came to the same realization in New York City. The three of them set out to prove it by injecting a group of male prisoners at  Sing Sing Correctional Facility  with antibody provided by Ortho, obtained by a fractionation technique developed by Pollack. [ 28 ]


Animal studies had previously been conducted by Dr. Pollack using a rabbit model of Rh. [ 29 ]  This model, named the rabbit HgA-F system, was an animal model of human Rh, and enabled Pollack's team to gain experience in preventing hemolytic disease in rabbits by giving specific HgA antibody, as was later done with Rh-negative mothers. One of the needs was a dosing experiment that could be used to determine the level of circulating Rh-positive cells in an Rh-negative pregnant female derived from her Rh-positive fetus. This was first done in the rabbit system, but subsequent human tests at the University of Manitoba conducted under Dr. Pollack's direction confirmed that anti-Rh o (D) immune globulin could prevent alloimmunization during pregnancy. [ citation needed ]


Ms. Marianne Cummins was the first at risk woman to receive a prophylactic injection of anti-Rh o (D) immune globulin (RHIG) after its regulatory approval. [ 30 ]  Clinical trials were set up in 42 centers in the US, Great Britain, Germany, Sweden, Italy, and Australia. RHIG was finally approved in England and the United States in 1968. [ 31 ]  The FDA approved the drug under the brand name RhoGAM, with a fixed dose of 300 μg, to be given within three days (72 hours) postpartum. Subsequently, a broader peripartum period was approved for dosing which included prophylaxis during pregnancy. Within a year, the antibody had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960s. By 1973, it was estimated that in the US alone, over 50,000 babies' lives had been saved. The use of Rh immune globulin to prevent the disease in babies of Rh negative mothers has become standard practice, and the disease, which used to claim the lives of 10,000 babies each year in the US alone, has been virtually eradicated in the developed world. In 1980,  Cyril Clarke ,  Ronald Finn ,  John G. Gorman , Vincent Freda, and William Pollack each received an  Albert Lasker Award  for Clinical Medical Research for their work on rhesus blood types and the prevention of Rh disease. [ citation needed ]


RUNX1  Familial Platelet Disorder  (RUNX1- FPD )  also known as Familial platelet disorder with associated myeloid malignancies, FPDMM ,  is a rare inherited disease caused by one of over 100 known  variants  (i.e.,  mutations ) in an individual’s  RUNX1  gene . Low platelets and dysfunctional platelets, which cause heavier than average bruising and bleeding, are hallmarks of the disorder. [ 1 ]  Individuals with  RUNX1 -FPD have a lifetime risk of being diagnosed with a  hematologic malignancy  of 35-45%. [ 2 ]


The most common hematologic malignancy diagnosed for these individuals is  acute myeloid leukemia (AML)  and  Myelodysplastic syndrome (MDS) . Additional HMs include  Acute lymphoblastic leukemia (ALL) ,  Chronic myelomonocytic leukemia ,  hairy-cell leukemia  and  Non-Hodgkin lymphoma (NHL) . [ 3 ] [ 4 ] [ 5 ]


RUNX1 -FPD patients often face a range of additional health issues including eczema, [ citation needed ]  arthritis, [ 6 ]  psoriasis, [ 7 ]  asthma, allergies, autoimmune disorders and gastrointestinal problems. [ 8 ]


Shwachman–Diamond syndrome  ( SDS ), or  Shwachman–Bodian–Diamond syndrome , is a rare congenital disorder characterized by  exocrine pancreatic insufficiency ,  bone marrow  dysfunction,  skeletal  and cardiac abnormalities and  short stature . After  cystic fibrosis  (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. It is associated with the  SBDS  gene and has autosomal recessive inheritance. [ citation needed ]


The syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome are  exocrine pancreatic dysfunction , hematologic abnormalities and growth retardation. Only the first two of these are included in the clinical diagnostic criteria. [ 1 ]


Shwachman–Diamond syndrome is characterized by an  autosomal recessive  mode of inheritance. The gene that is mutated in this syndrome,  SBDS , [ 2 ] [ 3 ] [ 4 ]  lies on the long arm of  chromosome 7  at  cytogenetic  position 7q11. [ 5 ] [ 6 ]  It is composed of five exons and has an associated  mRNA  transcript that is 1.6  kilobase  pairs in length. The  SBDS  gene resides in a block of genomic sequence that is locally duplicated on the chromosome. The second copy contains a non-functional version of the  SBDS  gene that is 97% identical to the original gene, but has accumulated inactivating mutations over time. It is considered to be a  pseudogene . In a study of 158 SDS families, 75% of disease-associated mutations appeared to be the result of  gene conversion , while 89% of patients harbored at least one such mutation. Gene conversion occurs when the intact  SBDS  gene and its pseudogene copy aberrantly  recombine  at  meiosis , leading to an incorporation of pseudogene-like sequences into the otherwise functional copy of the  SBDS  gene, thereby inactivating it. [ 7 ]


Two gene conversion mutations predominate in SDS patients.  One is a  splice site  mutation affecting the 5' splice site of  intron  two, while the second is an  exon  two  nonsense mutation . The marked absence of patients homozygous for the otherwise common nonsense mutation suggested that the SBDS gene is essential.  Consistent with this, knockout of the mouse gene leads to early embryonic lethality. [ 8 ]  This, in turn, suggests that the common splice site mutation seen in patients may be hypomorphic, i.e. that it results in only a partial loss of function, whereas the complete loss of SBDS function is likely to be lethal. [ 9 ]


The  SBDS  gene is expressed in all tissues and encodes a  protein  of 250  amino acid  residues.  A great deal of indirect evidence suggested that the SBDS protein may be involved in an aspect of cellular  RNA  metabolism or  ribosome  assembly or function. The wide occurrence of the gene in all  archaea  and  eukaryotes  supported a role for this protein in a very fundamental and evolutionarily conserved aspect of cellular biology. [ 10 ]  The homologous genes in archaea also tend to be present in conserved cluster enriched for RNA processing and ribosomal genes.  A specific function for SBDS in RNA metabolism or ribosome assembly or function is further supported by its localization to the  nucleolus , the nuclear subdomain where these processes occur. In line with this, the yeast homologue, SdoI, has been shown to be critical for maturation of pre-60S ribosomes, by effecting release and recycling of the nucleolar shuttling factor Tif6. [ 11 ]  This is required for 60S maturation and translational activation of ribosomes. It has also been shown that the  Dictyostelium discoideum  homologue catalyzes the removal of eukaryotic initiation factor 6 (eIF6), which is required for the translational activation of ribosomes. [ 12 ]   Cells from SDS patients were shown to have a defect in assembly of ribosome subunits. [ 13 ]


At present, it is not obvious how disruption of the basic cellular process of translation leads to the tissue- and organ-specific manifestations seen in SDS. However, unusual and combinations of tissues and organs are also affected in  Diamond–Blackfan anemia ,  X-linked   dyskeratosis congenita , and  cartilage–hair hypoplasia —three diseases that may also be linked to defective ribosome function.  Pleiotropic disease features may be the result of cell-specific effects of reduced levels of SBDS activity provided by hypomorphic mutations. [ citation needed ]


Initially, the clinical presentation of SDS may appear similar to  cystic fibrosis . However, CF can be excluded with a normal chloride in sweat test but faecal elastase as a marker of pancreatic function will be reduced. The variation, intermittent nature, and potential for long-term improvement of some clinical features make this syndrome difficult to diagnose. SDS may present with either  malabsorption , or hematological problems. Rarely, SDS may present with skeletal defects, including severe rib cage abnormalities that lead to difficulty in breathing. Diagnosis is generally based on evidence of exocrine pancreatic dysfunction and neutropenia. Skeletal abnormalities and short stature are characteristics that can be used to support the diagnosis. The  gene  responsible for the disease has been identified and  genetic testing  is now available. [ citation needed ]