Pancreatic exocrine insufficiency may be treated through pancreatic enzyme supplementation, [ 14 ]  while severe skeletal abnormalities may require surgical intervention. Neutropenia may be treated with  granulocyte-colony stimulating factor  (GCSF) to boost peripheral neutrophil counts. However, there is ongoing and unresolved concern that this drug could contribute to the development of  leukemia . Signs of progressive marrow failure may warrant  bone marrow transplantation  (BMT). This has been used successfully to treat hematological aspects of disease. However, SDS patients have an elevated occurrence of BMT-related adverse events, including  graft-versus-host disease  (GVHD) and toxicity relating to the pre-transplant conditioning regimen. In the long run, study of the gene that is mutated in SDS should improve understanding of the molecular basis of disease. This, in turn, may lead to novel therapeutic strategies, including  gene therapy  and other gene- or protein-based approaches. [ citation needed ]


A major goal of curative therapy for SDS is to reduce the risk of bone marrow failure and halt the progression of  malignant transformation  toward  myelodysplastic syndrome  (MDS) and  acute myeloid leukemia  (AML), the most detrimental complications of SDS.  Currently, there is no such therapy.  However, several emerging therapeutic strategies, including  gene therapy  and  antisense oligonucleotides  (ASOs), could potentially slow or prevent malignant transformation, at least in theory.  These new therapies have been proven effective for several rare diseases, including  metachromatic leukodystrophy  and  spinal muscular atrophy .  Several SDS patient groups are advocating for better therapies for SDS, [ 15 ] [ 16 ] [ 17 ] [ 18 ]  and one organization is focused on driving the therapy development efforts. [ 19 ]   The challenge is whether the SDS community can come together to support the required research, [ 20 ]  and whether the organizations can successfully execute a strategy that coordinates the efforts for new therapy development. [ 21 ]


It is thought to have an estimated incidence of 1 in 75,000 people. [ 22 ]


The disease was first described as a coherent clinical entity in May 1964 by Bodian, Sheldon, and Lightwood. [ 23 ]  It was subsequently described by Shwachman, Diamond, Oski, and Khaw in November of the same year. [ 24 ]  In 2001, linkage analysis in SDS families indicated that affected gene mapped to a large region of human chromosome seven. [ 25 ]  In 2002, this interval was refined to a region on the long arm of the  chromosome  next to the  centromere . [ 26 ]


In 2003, a team of researchers led by  Johanna Rommens  at the Hospital of Sick Children (SickKids) in Toronto, Canada, discovered mutations in the  SBDS  gene (Shwachman–Bodian–Diamond syndrome) were associated with disease. [ 7 ]


Shwachman–Diamond syndrome, less commonly known as Shwachman–Bodian–Diamond syndrome, is named for Harry Shwachman (1910 – September 12, 1986), an American physician, Martin Bodian (1912 – May 12, 1994), a British ophthalmologist who worked in  New York City , and  Louis Klein Diamond  (May 11, 1902 – June 14, 1999), an American pediatrician. [ citation needed ]


The  trauma triad of death  is a medical term describing the combination of  hypothermia ,  acidosis , and  coagulopathy . [ 1 ]  This combination is commonly seen in patients who have sustained severe  traumatic injuries  and results in a significant rise in the  mortality rate . [ 2 ]  Commonly, when someone presents with these signs,  damage control surgery  is employed to reverse the effects. [ citation needed ]


The three conditions share a complex relationship; each factor can compound the others, resulting in high mortality if this  positive feedback  loop continues uninterrupted. [ citation needed ]


Severe  bleeding  in trauma diminishes  oxygen delivery , and may lead to  hypothermia . This in turn can halt the  coagulation cascade , preventing  blood from clotting . In the absence of blood-bound oxygen and nutrients ( hypoperfusion ), the body's cells burn glucose  anaerobically  for energy, causing the release of  lactic acid ,  ketone bodies , and other  acidic  compounds into the blood stream, which lower the blood's  pH , leading to  metabolic acidosis . Such an increase in acidity damages the tissues and organs of the body and can reduce  myocardial performance , further reducing the oxygen delivery. [ citation needed ]


Tumor lysis syndrome  ( TLS ) is a group of  metabolic abnormalities  that can occur as a  complication  from the treatment of  cancer , where large amounts of  tumor  cells are killed off ( lysed ) from the treatment, releasing their contents into the  bloodstream . [ 1 ]  This occurs most commonly after the treatment of  lymphomas  and  leukemias  and in particular when treating  non-Hodgkin lymphoma ,  acute myeloid leukemia , and  acute lymphoblastic leukemia . [ 2 ] [ 3 ]  This is a potentially fatal complication and people at an increased risk for TLS should be closely monitored while receiving  chemotherapy  and should receive preventive measures and treatments as necessary. [ 4 ] [ 3 ]  TLS can also occur on its own (while not being treated with chemotherapy) although this is less common. [ 4 ] [ 5 ]


Tumor lysis syndrome is characterized by high blood potassium ( hyperkalemia ), high blood phosphate ( hyperphosphatemia ), low blood calcium ( hypocalcemia ), high blood uric acid ( hyperuricemia ), and higher than normal levels of blood urea nitrogen ( BUN ). [ 4 ]  These changes in blood  electrolytes  and  metabolites  are a result of the release of cellular contents of dying cells into the bloodstream. [ 4 ]  In this respect, TLS is analogous to  rhabdomyolysis , with comparable mechanism and blood chemistry effects but with different cause. In TLS, the breakdown occurs after  cytotoxic  therapy or from cancers with high cell turnover and tumor proliferation rates. [ 4 ]  The metabolic abnormalities seen in tumor lysis syndrome can ultimately result in serious complications such as  acute uric acid nephropathy ,  acute kidney failure ,  seizures ,  cardiac arrhythmias , and death. [ 6 ] [ 7 ]


Acute uric acid nephropathy  (AUAN) due to hyperuricosuria has been a dominant cause of acute kidney failure, but with the advent of effective treatments for hyperuricosuria, AUAN has become a less common cause than hyperphosphatemia.  [ citation needed ]  Two common conditions related to excess  uric acid ,  gout  and  uric acid nephrolithiasis , are not features of tumor lysis syndrome. [ citation needed ]


Risk factors for tumor lysis syndrome depend on several different characteristics of the patient, the type of cancer, and the type of chemotherapy used. [ 14 ]


Tumor characteristics:  Tumors with a high cell turnover rate, rapid growth rate, and high tumor bulk tend to be more associated with the development of tumor lysis syndrome. The most common tumors associated with this syndrome are poorly differentiated lymphomas (such as  Burkitt's lymphoma ), other  Non-Hodgkin Lymphomas  (NHL),  acute lymphoblastic leukemia  (ALL), and  acute myeloid leukemia  (AML). [ 3 ]   Other cancers (such as  melanoma ) have also been associated with TLS but are less common.


Patient characteristics:  Certain patient-related factors can affect the development of clinical tumor lysis syndrome. These factors include elevated baseline serum  creatinine ,  kidney failure , dehydration, and other issues affecting urinary flow or the acidity of urine. [ 14 ]


Chemotherapy characteristics:  Chemo-sensitive tumors, such as lymphomas, carry a higher risk for the development of tumor lysis syndrome. Those tumors that are more responsive to a chemotherapy agent carry a higher TLS risk. [ 7 ]  Usually, the precipitating medication regimen includes combination  chemotherapy , but TLS can be triggered in cancer patients by  steroid  treatment alone, and sometimes without any treatment—in this case the condition is referred to as "spontaneous tumor lysis syndrome". [ 13 ]


TLS should be suspected in people with large tumor burden who develop acute kidney failure along with hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL).  [ medical citation needed ]  (Most other acute kidney failure occurs with uric acid < 12 mg/dL and phosphate < 6 mg/dL).  [ citation needed ]  Acute uric acid nephropathy is associated with little or no urine output.  [ citation needed ]  The  urinalysis  may show uric acid crystals or amorphous urates.  [ citation needed ]  The hypersecretion of uric acid can be detected with a high urine uric acid - creatinine ratio > 1.0, compared to a value of 0.6–0.7 for most other causes of acute kidney failure. [ citation needed ]


In 2004, Cairo and Bishop defined a classification system for tumor lysis syndrome. [ 15 ]


A grading scale (0–5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.


In 2011, Howard proposed a refinement of the standard Cairo-Bishop definition of TLS accounting for 2 limitations: [ 2 ]


Moreover, any symptomatic hypocalcemia should constitute clinical TLS. [ 2 ]


It is important to prevent life-threatening manifestations associated with TLS which include acute kidney injury, hyperkalemia (which may cause cardiac arrhythmias), and or hypocalcemia (which may cause cardiac arrhythmias and neuromuscular irritability). [ 2 ]


Acute kidney injury:  Patients at risk for developing TLS (e.g. patients about to receive chemotherapy for a cancer with a high cell turnover rate, especially  lymphomas  and  leukemias ) should receive appropriate intravenous hydration in order to improve blood flow to the kidneys, maximize urine output, and ultimately prevent precipitation of uric acid crystals that can lead to acute kidney injury. [ 2 ] [ 4 ]  A diuretic may also be indicated to further increase urine output in addition to intravenous hydration. [ 2 ] [ 4 ]  Another approach to prevent damage to the kidneys is to prevent the buildup of uric acid during TLS, and this can be accomplished with use of  allopurinol  or  rasburicase . [ 2 ]   Allopurinol  (a  xanthine oxidase  inhibitor, which inhibits uric acid production) works by preventing the formation of uric acid following tumor cell lysis. [ 4 ] [ 13 ]   Rasburicase  is a synthetic  urate oxidase  enzyme and acts by degrading uric acid. No current guidelines endorse the concurrent use of allopurinol and rasburicase. [ 16 ] [ 17 ]  It is not recommended to alkalinize urine in the management of TLS: although doing so increases the solubility of urste, it also creates calcium phosphate crystals. [ 2 ] [ 4 ]


Hyperkalemia:  Monitoring potassium levels in the blood frequently and cardiac monitoring (given the risk of cardiac arrhythmias) are important components in the prevention of adverse consequences in TLS. [ 2 ]  Other strategies, such as limiting oral intake of potassium, and excreting potassium through the gastrointestinal tract using agents such as oral sodium polystyrene sulfonate, can be beneficial. [ 2 ] [ 4 ]   Insulin  therapy (in conjunction with glucose administration) as well as  beta-receptor agonists  (such as  albuterol ) can also be used, but are temporary interventions, [ 2 ]  and potassium is not excreted from the body.  [ citation needed ]   Hemodialysis  and  hemofiltration  can also be used as options to remove potassium from the bloodstream when hyperkalemia is present. [ 2 ]


Hypocalcemia:  Hyperphosphatemia is a common finding in TLS, and high phosphorus levels can in turn contribute to hypocalcemia. Therefore, phosphate binders may be beneficial in preventing this form of hypocalcemia. [ 2 ]


Treatment is first targeted at the specific metabolic disorder.


In general,  rasburicase  and hydration are the mainstays of treatment in patients with clinical evidence of tumor lysis syndrome. [ 18 ]  A  loop diuretic  may also be indicated to maintain appropriate production of urine by the kidneys. [ 18 ]  Further treatment is targeted towards the specific metabolic abnormalities present in patients with TLS (see "main articles" linked above). Mild  hyperkalemia  without symptoms can be treated with a  loop diuretic  and sodium  polystyrene sulfonate , while a temporizing agent such as rapid acting  insulin  (in conjunction with glucose) and an agent to stabilize cardiac membranes such as  calcium carbonate  may be given in cases of severe hyperkalemia. [ 18 ]  Concerning symptoms related to hypocalcemia (e.g. seizures) in TLS patients can be treated with  calcium gluconate . [ 18 ]  Tumor lysis patients may ultimately also require  renal replacement therapy  such as through hemodialysis if indicated. [ 18 ]


The rate of mortality from tumor lysis syndrome may vary widely depending on the type of underlying malignancy. [ 19 ]  However, the occurrence of acute kidney injury is concerning given the high mortality that is generally associated with it. [ 2 ]


X-linked thrombocytopenia , also referred to as  XLT  or  thrombocytopenia 1 , is an inherited clotting disorder that primarily affects males. It is a  WAS -related disorder, meaning it is caused by a mutation in the  Wiskott–Aldrich syndrome  ( WAS ) gene, which is located on the short arm of the  X chromosome . [ 1 ]   WAS -related disorders include Wiskott–Aldrich syndrome, XLT, and X-linked congenital  neutropenia  (XLN). Of the  WAS -related disorders, X-linked thrombocytopenia is considered to be the milder  phenotype . Between 1 and 10 per million males worldwide are affected with this disorder. Females may be affected with this disorder but this is very rare since females have two X chromosomes and are therefore typically carriers of the mutation.


X-linked thrombocytopenia is typically diagnosed in infancy. The disease presents as a bleeding disorder with easy bruising, mucosal bleeding, such as nosebleeds, and mild to severe anemia.  Anemia  is a condition in which there is an insufficient number of red blood cells to carry adequate levels of oxygen to the body's tissues. [ 2 ]  X-linked thrombocytopenia is considered to be the milder phenotype of the  WAS -related disorders. As age increases, the severity of symptoms tends to decrease. However, individuals with X-linked thrombocytopenia have an increased risk for life-threatening brain hemorrhages and spontaneous bleeding. [ citation needed ]


X-linked thrombocytopenia is inherited on the  X chromosome . Females that are carriers will have a 50% chance of passing the  WAS  gene mutation on to their male offspring. Female offspring also have a 50% chance of receiving the mutated gene from their mothers and are considered carriers in that event. Males with X-linked thrombocytopenia will not pass the condition to their sons since they pass their Y chromosome on to any male offspring. However, any daughters males with this condition have will be carriers. [ citation needed ]


X-linked thrombocytopenia primarily affects the circulatory system, specifically the  platelets  in the blood. Platelets are cell fragments in the blood that aid in clotting. Platelets are produced in the  bone marrow . Normal platelet counts range from 150,000 to 450,000 platelets per μL of blood. [ 3 ]  Individuals with XLT usually have drastically reduced platelet counts, typically less than 70,000 platelets per μL of blood. Not only are there fewer platelets circulating, but individuals with XLT also have smaller platelets. Fewer and smaller platelets causes the efficacy of the clotting mechanism in the body to be seriously compromised, which can lead to bruising and bleeding. X-linked thrombocytopenia is caused by a  mutation  of the  WAS  gene. This mutation causes the decreased, absent, or altered  Wiskott–Aldrich syndrome protein  (WASp). Normal WASp is involved in relaying signals from the  cell membrane  to the actin  cytoskeleton . If WASp is decreased, absent, or altered, then the  hematopoietic  cells it is found in will show signaling and cytoskeleton abnormalities. [ citation needed ]


This form of thrombocytopenia is inherited on X chromosome, thus individuals with this disorder are typically males. In regards to the sex chromosomes, males have one X chromosome and one  Y chromosome  while females have two X chromosomes. Because males only have one X chromosome, if they receive an X chromosome with a  WAS  gene mutation from their mother, then they will show phenotype of the condition. Females can be carriers for this disorder, which means that they have one normal X chromosome and one X chromosome with the  WAS  gene mutation. Females that are carriers do not show any signs or symptoms of X-linked thrombocytopenia. [ 4 ]


Males with X-linked thrombocytopenia are also susceptible to severe infections, bleeding,  autoimmune diseases  and malignancies.


Aside from observing the symptoms characteristic of X-linked thrombocytopenia in infancy (easy bruising, mild anemia, mucosal bleeding), molecular  genetic testing  would be done to confirm the diagnosis. Furthermore,  flow cytometry  or  western blotting  would be used to test for decreased or absent amounts of WASp. Family history would also assist in diagnosis, with specific attention to maternally related males with  WAS -related disorders. Because  WAS -related disorders are phenotypically similar, it is important to confirm the absence of the diagnostic criteria for Wiskoff-Aldrich syndrome at the outset. [ 4 ]  These diagnostic criteria include  eczema ,  lymphoma ,  autoimmune disorder , recurrent bacterial or viral infections, family history of maternally related males with a  WAS -related disorder, and absent or decreased  WASp . X-linked congenital neutropenia can be diagnostically distinguished from XLT with persistent  neutropenia , arrested development of the bone marrow, and normal  WASp  expression. [ citation needed ]


Treatment for individuals with X-linked thrombocytopenia is typically focused on managing symptoms of the disorder.  Splenectomy  has been shown to improve platelet counts but also significantly increases the risk of life-threatening infections for patients with XLT. Therefore, these individuals must take antibiotics for the rest of their life to avoid fatal  bacteremia . In the event of significant bleeding, platelet  transfusions  should be administered. Circumcision should be avoided for infant males with XLT due to the risk of bleeding and infection. Regular follow ups to track blood counts should be utilized as well as confirming that any medications, over the counter or prescription, will not interfere with platelet functioning. [ citation needed ]


Recent studies have found that the life expectancy of males with XLT is not significantly affected. [ 5 ]  Individuals with XLT typically experience milder symptoms than those with other  WAS -related disorders. For this reason, the long term prognosis for individuals with XLT is generally positive as long as symptoms are managed appropriately. Enhanced treatment methods in the past two decades have significantly improved the prognosis as well. [ citation needed ]


Recent research has suggested that  hematopoietic stem cell transplantation  may be a treatment option for patients with XLT despite associated risks. [ 6 ]  Other studies have shown that treatment with  corticosteroids  or intravenous  immunoglobulin  in any dose or duration may have a beneficial impact on platelet counts, although transiently. [ 7 ]  Furthermore, research has shown that  splenectomy  may not be a good treatment option for patients with XLT as it increases the risk of severe infections. This same research showed that patients with XLT have a high overall survival rate but they are at risk for severe life-threatening complications associated with this disorder, such as serious bleeding events and malignancies. [ 5 ]


A  blood test  is a  laboratory  analysis performed on a  blood  sample that is usually extracted from a  vein  in the arm using a  hypodermic needle , or via  fingerprick . Multiple tests for specific blood components, such as a  glucose test  or a  cholesterol test , are often grouped together into one  test panel  called a  blood panel  or  blood work . Blood tests are often used in  health care  to determine  physiological  and  biochemical  states, such as  disease ,  mineral  content,  pharmaceutical drug  effectiveness, and organ function. Typical  clinical  blood panels include a  basic metabolic panel  or a  complete blood count . Blood tests are also used in  drug tests  to detect drug abuse.


A  venipuncture  is useful as it is a  minimally invasive  way to obtain  cells  and  extracellular fluid  ( plasma ) from the body for analysis. Blood flows throughout the body, acting as a medium that provides  oxygen  and nutrients to tissues and carries waste products back to the excretory systems for disposal. Consequently, the state of the bloodstream affects or is affected by, many medical conditions. For these reasons, blood tests are the most commonly performed  medical tests . [ 1 ]


If only a few drops of blood are needed, a  fingerstick  is performed instead of a  venipuncture . [ 2 ]


Indwelling arterial, central venous and peripheral venous lines can also be used to draw blood. [ 3 ]


Phlebotomists ,  laboratory practitioners  and  nurses  are those in charge of extracting blood from a patient. However, in special circumstances, and/or emergency situations,  paramedics  and  physicians  extract the blood. Also,  respiratory therapists  are trained to extract arterial blood to examine  arterial blood gases . [ 4 ] [ 5 ]


A  basic metabolic panel  measures  sodium ,  potassium ,  chloride ,  bicarbonate ,  blood urea nitrogen  (BUN),  magnesium ,  creatinine ,  glucose , and sometimes  calcium . Tests that focus on cholesterol levels can determine  LDL  and  HDL cholesterol  levels, as well as  triglyceride  levels. [ 6 ]


Some tests, such as those that measure glucose or a  lipid profile , require fasting (or no food consumption) eight to twelve hours prior to the drawing of the blood sample. [ 7 ]


For the majority of tests, blood is usually obtained from the patient's vein. Other specialized tests, such as the  arterial blood gas  test, require blood extracted from an  artery . Blood gas analysis of arterial blood is primarily used to monitor  carbon dioxide  and  oxygen  levels related to  pulmonary  function, but is also used to measure blood  pH  and  bicarbonate  levels for certain metabolic conditions. [ 8 ]


While the regular  glucose test  is taken at a certain point in time, the  glucose tolerance test  involves repeated testing to determine the rate at which  glucose  is processed by the body. [ 9 ]


Blood tests are also used to identify autoimmune diseases and  Immunoglobulin E -mediated food allergies (see also  Radioallergosorbent test ). [ 10 ] : 1118


Blood tests results should always be interpreted using the ranges provided by the laboratory that performed the test. Example ranges are shown below.


Upon completion of a blood test analysis, patients may receive a report with blood test abbreviations. Examples of common blood test abbreviations are shown below.


(UK: FBC)


(UK: Full Blood Count)


In 2008, scientists announced that the more cost effective  saliva testing  could eventually replace some blood tests, as saliva contains 20% of the proteins found in blood. [ 15 ]  Saliva testing may not be appropriate or available for all markers. For example, lipid levels cannot be measured with saliva testing.


In February 2011, Canadian researchers at the University of Calgary's Schulich School of Engineering announced a microchip for blood tests. Dubbed a microemulsion, a droplet of blood captured inside a layer of another substance. It can control the exact size and spacing of the droplets. The new test could improve the efficiency, accuracy, and speed of laboratory tests while also doing it cheaply. [ 16 ]


In March 2011, a team of researchers from  UC Berkeley ,  DCU  and  University of Valparaíso  have developed  lab-on-a-chip  that can diagnose diseases within 10 minutes without the use of external tubing and extra components. It is called Self-powered Integrated Microfluidic Blood Analysis System (SIMBAS). It uses tiny trenches to separate blood cells from plasma (99 percent of blood cells were captured during experiments). Researchers used plastic components, to reduce manufacturing costs. [ 17 ] [ 18 ]


The  Abelin reaction  is a qualitative reaction for demonstrating the presence of  arsphenamine  and  neoarsphenamine  in  blood  and  urine .


It is named for  Isaak Abelin , Swiss physiologist. [ 1 ]


Absolute neutrophil count  (ANC) is a measure of the number of  neutrophil granulocytes [ 1 ]  (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the  blood . Neutrophils are a type of  white blood cell  that fights against  infection .


The ANC is almost always a part of a larger  blood panel  called the  complete blood count . The ANC is calculated from measurements of the total number of white blood cells (WBC), usually based on the combined percentage of mature neutrophils (sometimes called "segs", or segmented cells) and  bands , which are immature neutrophils.


The  reference range for ANC  in adults varies by study, but 1500 to 8000 cells per microliter is typical. An ANC less than 1500 cells/μL is defined as neutropenia and increases risk of infection.   Neutropenia  is the condition of a low ANC, and the most common condition where an ANC would be measured is in the setting of chemotherapy for cancer. [ citation needed ]


Neutrophilia  indicates an elevated count.  While many clinicians refer to the presence of neutrophilia as a "left shift", this is imprecise, as a left shift indicates the presence of immature neutrophil forms, [ citation needed ]  but neutrophilia refers to the entire mass of neutrophils, both mature and immature.  Neutrophilia can be indicative of:


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)}


or


ANC = ( Absolute-Polys + Absolute-Bands )


In some cases, a ratio is reported in addition to the sum. This is known as the "I/T ratio". [ 3 ] [ 4 ]


The  ACTH test  (also called the  cosyntropin ,  tetracosactide , or  Synacthen test ) is a  medical test  usually requested and interpreted by  endocrinologists  to assess the functioning of the  adrenal glands ' stress response by measuring the adrenal response to  adrenocorticotropic hormone  (ACTH; corticotropin) or another  corticotropic   agent  such as  tetracosactide  (cosyntropin, tetracosactrin; Synacthen) or  alsactide  (Synchrodyn). [ 1 ] [ 2 ]  ACTH is a hormone produced in the  anterior pituitary gland  that stimulates the adrenal glands to release  cortisol ,  dehydroepiandrosterone  (DHEA),  dehydroepiandrosterone sulfate  (DHEA-S), and  aldosterone . [ 3 ]


During the test, a small amount of synthetic ACTH is injected, and the amount of cortisol (and sometimes aldosterone) that the adrenals produce in response is measured. [ 4 ]  This test may cause mild side effects in some individuals. [ 5 ] [ 6 ]


This test is used to diagnose or exclude primary and secondary  adrenal insufficiency ,  Addison's disease , and related conditions. [ 2 ]  In addition to quantifying adrenal insufficiency, the test can distinguish whether the cause is adrenal (low cortisol and aldosterone production) or pituitary (low ACTH production). [ 1 ]  The  insulin tolerance test  is recognized as the gold standard assay of adrenal insufficiency, but due to the cumbersome requirement for a two-hour test and the risks of seizures or myocardial infarction, the ACTH stimulation test is commonly used as an easier, safer, though not as accurate, alternative. [ 7 ]  The test is extremely sensitive (97% at 95% specificity) to primary adrenal insufficiency, but less so to secondary adrenal insufficiency (57–61% at 95% specificity); while secondary adrenal insufficiency may thus be dismissed by some interpreters on the basis of the test, additional testing may be called for if the probability of secondary adrenal insufficiency is particularly high. [ 1 ]


Adrenal insufficiency is a potentially life-threatening condition. Treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in apparent adrenal crisis. [ 8 ]


This test can be given as a  low-dose short test , a  conventional-dose short test , or as a  prolonged-stimulation test . [ citation needed ]


In the low-dose short test, 1 μg of an ACTH drug is injected into the patient. In the conventional-dose short test, 250 μg of drug are injected. Both of these short tests last for about an hour and provide the same information. Studies have shown the cortisol response of the adrenals is the same for the low-dose and conventional-dose tests. [ 9 ] [ 10 ]


The prolonged-stimulation test, which is also called a  long conventional-dose test , can last up to 48 hours. This form of the test can differentiate between primary, secondary, and tertiary adrenal insufficiency. This form of the test is rarely performed because earlier testing of cortisol and ACTH levels in association with the short test may provide all the necessary information. [ 8 ]


The test should not be given if on  glucocorticoids  or adrenal extract supplement, as these will affect test results. Stress and recently administered  radioisotope  scans [ citation needed ]  can artificially increase levels and may invalidate test results.  Spironolactone ,  contraceptives ,  licorice ,  estrogen ,  androgen  (including DHEA) and  progesterone  therapy may also affect both aldosterone and cortisol stimulation test results. To stimulate aldosterone, consumption of salt should be reduced to a minimum, and foods high in sodium avoided for 24 hours prior to testing. Women should ideally undergo testing during the first week of their menstrual cycle as aldosterone (and occasionally cortisol) may be falsely elevated in the luteal cycle secondary to progesterone inhibition, leading to a compensatory rise in aldosterone levels. [ 11 ]


Traditionally, cortisol and ACTH levels (separate lavender top tube) are drawn at baseline (time = 0). Next, synthetic ACTH or another corticotropic agent is injected IM or IV, depending on the agent. [ 12 ]  Approximately 20 mL of heparinized venous blood is collected at 30 and 60 minutes after the synthetic ACTH injection to measure cortisol levels. [ 13 ] [ 14 ]


ACTH samples are kept on ice and sent immediately to the laboratory, whereas cortisol does not need to be kept on ice. [ 15 ]


Commonly reported reactions are nausea, anxious sweating, dizziness, itchy skin, redness and or swelling of injection site, palpitations (a fast or fluttering heart beat), and facial flushing (may also include arms and torso), but should disappear within a few hours. [ 5 ] [ 6 ]  Rarely seen, but serious side effects include rash, fainting, headache, blurred vision, severe swelling, severe dizziness, trouble breathing, irregular heartbeat. [ 6 ]


In healthy individuals, the cortisol level should increase above 18–20 μg/dl within 60 minutes on a 250 mcg cosyntropin stimulation test. [ 16 ]


In Addison's disease, both the cortisol and  aldosterone  levels are low, and the cortisol will not rise during the cosyntropin stimulation test [ citation needed ]


In secondary adrenal insufficiency, due to exogenous steroid administration suppressing pituitary production of ACTH or due to primary pituitary disorder causing insufficient ACTH production, the adrenal glands will  atrophy  over time and cortisol production will fall and patients will fail stimulation testing. Early in the development of secondary adrenal insufficiency, the adrenals may not have atrophied and can still stimulate, resulting in a normal cosyntropin stimulation test. [ 17 ]


If secondary adrenal insufficiency is diagnosed, the insulin tolerance test (ITT) or the CRH ( corticotropin-releasing hormone ) stimulation test can be used to distinguish between a hypothalamic (tertiary) and pituitary (secondary) cause but is rarely used in clinical practice. [ 17 ]


Measuring a morning, fasting ACTH level helps assess for the etiology of adrenal insufficiency. [ citation needed ]


ACTH will be high [ 13 ]  – usually well above upper limits of reference range.


ACTH will be low [ 13 ]  – usually below 35, but most people with secondary fall within the range limit. This is inappropriately normal for the low cortisol level.


In some cases, the actual cause of low ACTH is from low CRH in the hypothalamus. It is possible to have separate ACTH and CRH impairment such as can happen in a head injury. [ 18 ]


The ACTH stimulation test is occasionally used to test adrenal production of aldosterone at the same time as cortisol to also help in determining if primary (hyperreninemic) or secondary (hyporeninemic)  hypoaldosteronism  is present. [ 4 ]  Human ACTH has a slight stimulatory effect on aldosterone, [ 19 ]  but the amount of synthetic ACTH given in the stimulation is equivalent to more than a whole days production of natural ACTH, so the aldosterone response can be easily measured in blood serum. [ 20 ]  Same as cortisol, aldosterone should double from a respectable base value (around 20 ng/dl, must fast salt 24 hours and sit upright for blood draw) in a healthy individual. [ citation needed ]


The aldosterone response in the ACTH stimulation test is blunted or absent in patients with primary adrenal insufficiency including Addison's disease. [ 4 ]  The base value is usually in the mid-teens or less and rise to less than double the base value thus indicating primary hypoaldosteronism ( sodium  low,  potassium  and renin  enzyme  will be high) and is an indicator of primary adrenal insufficiency or Addison's disease. [ citation needed ]


Aldosterone response of several factors from a low base value. This factoring indicates secondary hypoaldosteronism (sodium low, potassium and renin enzyme will be low). Usually doubling to quadrupling from a low base aldosterone value is what is seen in secondary adrenal insufficiency. Decoupling of aldosterone in the ACTH stimulation test is possible (i.e. 2 ng/dl stimming to 20). [ 21 ]  A result of doubling or more of aldosterone may help in tandem with a cortisol stimulation that doubled or more confirm a diagnosis of secondary adrenal insufficiency. In rare cases, an aldosterone stimulation which did not double, but with the presence of low potassium, low renin and low ACTH indicates atrophy of aldosterone production from the prolonged lack of renin.


Similar to the cortisol stimulation in ACTH deficiency, the test interpreter may lack knowledge of how to properly interpret for secondary hypoaldosteronism and think a result of aldosterone doubling or more from a low base value is good.


Recent data showed that Synacthen test results can be used to predict future recovery of HPA axis function in patients with reversible causes of Adrenal Insufficiency. [ 22 ]


The test is also used to diagnose  hypoadrenocorticism in dogs  and sometimes cats. [ 27 ] [ 28 ] [ 29 ]


The  activated protein C resistance  ( APCR )  test  is a  coagulation test  used in the evaluation and  diagnosis  of  activated protein C (APC) resistance , a form of  hypercoagulability . [ 1 ] [ 2 ]  Hereditary APC resistance is usually caused by the  factor V Leiden  mutation, whereas acquired APC resistance has been linked to  antiphospholipid antibodies ,  pregnancy , and  estrogen  therapy. [ 3 ] [ 4 ] [ 5 ] [ 6 ]  APC resistance can be measured using either an  activated partial thromboplastin time  (aPTT)-based test or an  endogenous thrombin potential (ETP)-based test . [ 5 ] [ 4 ] [ 2 ]


The aPTT-based APC resistance test involves a modified aPTT test performed in the presence and absence of  activated protein C  (APC). [ 1 ] [ 5 ]  The ratio of these aPTT values is calculated and is called the APC sensitivity ratio (APCsr) or simply APC ratio (APCr). [ 1 ] [ 5 ]  This ratio is inversely related to the degree of APC resistance. [ 7 ]  The ETP-based APC resistance test involves the addition of APC to a  thrombin generation assay  (TGA). [ 5 ]  This results in an inhibition of  thrombin generation  as measured by reduction of the  endogenous thrombin potential  (ETP; area under the thrombin generation curve). [ 5 ]  The result is expressed as a normalized APC sensitivity ratio (nAPCsr), which corresponds to the ratio of the ETP measured in the presence and absence of APC divided by the same ratio in reference plasma. [ 5 ]  nAPCsr values range from 0 to 10. [ 5 ]  Opposite to the case of the APCsr with the aPTT-based APC resistance test, higher nAPCsr values indicate greater APC resistance. [ 5 ] [ 8 ]  This is the result of the fact that APC prolongs the aPTT but inhibits thrombin generation. [ 8 ]


Whereas the aPTT-based APC resistance test only measures the initiation phase of  coagulation , the ETP-based test is a  global assay  and measures the initiation, propagation, and termination phases of coagulation. [ 5 ] [ 9 ]  The initiation phase accounts for less than 5% of total  thrombin generation , making aPTT-based tests poorly indicative of hypercoagulability in general. [ 10 ] [ 11 ]  The aPTT-based assay is more sensitive to levels of  prothrombin  and  factor VIII , whereas the ETP-based test is more sensitive to levels of  tissue factor pathway inhibitor  (TFPI) and  protein S . [ 5 ]  The ETP-based test has traditionally been performed using methods such as the  calibrated automated thrombogram  (CAT) and has been limitedly available due to its technical difficulty. [ 2 ]  Recently however, a fully automated commercial test system called the  ST Genesia  has been introduced, and it has been said that this should allow for adoption of TGAs and ETP-based APC resistance tests in routine clinical settings. [ 2 ] [ 12 ]


Estrogens  are well known to increase APC resistance, which has been described as acquired APC resistance. [ 2 ] [ 5 ] [ 4 ] [ 13 ] [ 14 ]  However, the aPTT-based APC resistance test is much less sensitive to the procoagulatory effects of estrogens than is the ETP-based test. [ 13 ] [ 14 ] [ 5 ] [ 4 ] [ 2 ] [ 15 ]   Pregnancy [ 7 ]  and  ethinylestradiol  (EE)-containing  combined birth control pills  increase APC resistance as measured by either the aPTT- or ETP-based test. [ 4 ] [ 5 ] [ 15 ]  EE-containing birth control pills show different degrees of influence on the ETP-based test depending on the  progestin , which may be due to varying degrees of  androgenic  antagonism of ethinylestradiol-mediated procoagulation. [ 5 ] [ 4 ]  In contrast to EE-containing birth control pills, studies have not found increased APC resistance with  menopausal hormone therapy  or with  estetrol - or  estradiol-containing birth control pills  using the aPTT-based test, though increased APC resistance has been shown with the ETP-based test. [ 14 ]  The increase in APC resistance is much greater with  oral  estrogens than with  transdermal   estradiol . [ 14 ]  Increased APC resistance with both the aPTT-based and ETP-based tests has been observed with  feminizing hormone therapy  in  transgender women , which involves higher doses of estradiol than are used in other contexts. [ 16 ] [ 17 ]  EE produces a much stronger increase in APC resistance than does estradiol. [ 18 ] [ 17 ]  In relation to this, ethinylestradiol is associated with a higher risk of  venous thromboembolism  (VTE) than is estradiol. [ 18 ] [ 19 ] [ 20 ]


The aPTT-based APC resistance test was developed in 1993, while the ETP-based test was developed in 1997. [ 5 ]  For many years, the ETP-based APC resistance test suffered from a lack of  standardization  which hampered study-to-study comparison. [ 21 ]  By 2020 however, a validated methodology was developed aiming to propose a standardized and  harmonized  scale for ETP-based APC resistance, the normalized activated protein C sensitivity ratio (nAPCsr). [ 21 ]


Anisochromia  is a marked variability in the color density of  erythrocytes  (red blood cells), which indicates unequal  hemoglobin  content among the red blood cells.


Sideroblastic anemia  or other severe forms of anemia may cause anisochromatism. It can also be seen after blood transfusions are administered, because blood products from multiple people may have different chromacity. [ 1 ] [ 2 ]


Anti-neutrophil cytoplasmic antibodies  ( ANCAs ) are a group of  autoantibodies , mainly of the  IgG  type, against  antigens  in the  cytoplasm  of  neutrophils  (the most common type of  white blood cell ) and  monocytes . They are detected as a  blood test  in a number of  autoimmune disorders , but are particularly associated with systemic  vasculitis , so called ANCA-associated vasculitides (AAV). [ 1 ]


Immunofluorescence  (IF) on ethanol-fixed neutrophils is used to detect ANCA, although formalin-fixed neutrophils may be used to help differentiate ANCA patterns. ANCA can be divided into four patterns when visualised by IF; cytoplasmic ANCA (c-ANCA), C-ANCA (atypical), perinuclear ANCA (p-ANCA) and atypical ANCA (a-ANCA), also known as x-ANCA. c-ANCA shows cytoplasmic granular fluorescence with central interlobular accentuation. C-ANCA (atypical) shows cytoplasmic staining that is usually uniform and has no interlobular accentuation. p-ANCA has three subtypes, classical p-ANCA, p-ANCA without nuclear extension and granulocyte specific-antinuclear antibody (GS-ANA). Classical p-ANCA shows perinuclear staining with nuclear extension, p-ANCA without nuclear extension has perinuclear staining without nuclear extension and GS-ANA shows nuclear staining on granulocytes only. a-ANCA often shows combinations of both cytoplasmic and perinuclear staining. [ 2 ]


The c-ANCA antigen is specifically  proteinase 3  (PR3). p-ANCA antigens include  myeloperoxidase  (MPO) and bacterial permeability increasing factor  Bactericidal/permeability-increasing protein  (BPI). Other antigens exist for c-ANCA (atypical), however many are as yet unknown. Classical p-ANCA occurs with antibodies directed to MPO. p-ANCA without nuclear extension occurs with antibodies to BPI,  cathepsin G ,  elastase ,  lactoferrin  and  lysozyme . GS-ANA are antibodies directed to granulocyte specific nuclear antigens. Atypical ANCA are thought to be antigens similar to that of the p-ANCAs, however may occur due to differences in neutrophil processing. [ 2 ]


Other less common antigens include  HMG1  (p-ANCA pattern),  HMG2  (p-ANCA pattern),  alpha enolase  (p and c-ANCA pattern),  catalase  (p and c-ANCA pattern),  beta glucuronidase  (p-ANCA pattern),  azurocidin  (p and c-ANCA pattern),  actin  (p and a-ANCA) and  h-lamp-2  (c-ANCA). [ 2 ]


Enzyme-linked immunosorbent assay  (ELISA) is used in diagnostic laboratories to detect ANCAs. Although IF can be used to screen for many ANCAs, ELISA is used to detect antibodies to individual antigens. The most common antigens used on an ELISA  microtitre plate  are MPO and PR3, which are usually tested for after a positive IF test. [ 3 ]


It is poorly understood how ANCA are developed, although several hypotheses have been suggested. There is probably a genetic contribution, particularly in genes controlling the level of immune response – although genetic susceptibility is likely to be linked to an environmental factor, some possible factors including vaccination or exposure to silicates. Two possible mechanisms of ANCA development are postulated, although neither of these theories answers the question of how the different ANCA specificities are developed, and there is much research still being undertaken on the development of ANCA. [ 4 ]


Microbial  superantigens  are molecules expressed by bacteria and other microorganisms that have the power to stimulate a strong immune response by activation of  T-cells . These molecules generally have regions that resemble self-antigens that promote a residual autoimmune response – this is the theory of molecular mimicry.  Staphylococcal  and  streptococcal   superantigens  have been characterized in autoimmune diseases – the classical example in post group A streptococcal  rheumatic heart disease , where there is similarity between  M proteins  of  Streptococcus pyogenes  to cardiac  myosin  and  laminin . It has also been shown that up to 70% of patients with  granulomatosis with polyangiitis  are chronic nasal carriers of  Staphylococcus aureus , with carriers having an eight times increased risk of  relapse . [ 4 ]   This would therefore be considered a  type II hypersensitivity  reaction. [ citation needed ]


Neutrophil  apoptosis , or programmed cell death, is vital in controlling the duration of the early inflammatory response, thus restricting damage to tissues by the neutrophils. ANCA may be developed either via ineffective apoptosis or ineffective removal of apoptotic cell fragments, leading to the exposure of the immune system to molecules normally sequestered inside the cells. This theory solves the paradox of how it could be possible for antibodies to be raised against the intracellular antigenic targets of ANCA. [ 4 ]


ANCAs are associated with small vessel  vasculitides  including  granulomatosis with polyangiitis ,  microscopic polyangiitis ,  primary pauci-immune necrotizing crescentic glomerulonephritis  (a type of renal-limited microscopic polyangiitis),  eosinophilic granulomatosis with polyangiitis  and drug induced vasculitides. ANCA-associated vasculitides (AAV) have new classification criteria, updated in 2022. [ 5 ] [ 6 ]
PR3 directed c-ANCA is present in 80-90% of granulomatosis with polyangiitis, 20-40% of microscopic polyangiitis, 20-40% of pauci-immune crescentic glomerulonephritis and 35% of eosinophilic granulomatosis with polyangiitis. c-ANCA (atypical) is present in 80% of cystic fibrosis (with BPI as the target antigen) and also in  inflammatory bowel disease ,  primary sclerosing cholangitis  and  rheumatoid arthritis  (with antibodies to multiple antigenic targets). p-ANCA with MPO specificity is found in 50% of microscopic polyangiitis, 50% of primary pauci-immune necrotizing crescentic glomerulonephritis and 35% of eosinophilic granulomatosis with polyangiitis. p-ANCA with specificity to other antigens are associated with inflammatory bowel disease, rheumatoid arthritis, drug-induced vasculitis,  autoimmune liver disease , drug induced syndromes and parasitic infections. Atypical ANCA is associated with drug-induced systemic vasculitis, inflammatory bowel disease and rheumatoid arthritis. [ 3 ] [ 7 ]  The ANCA-positive rate is much higher in patients with type 1 diabetes mellitus than in healthy individuals. [ 8 ]


Levamisole , which is a common adulterant of  cocaine , can cause an ANCA positive vasculitis. [ 9 ]


The presence or absence of ANCA cannot indicate presence or absence of disease and results are correlated with clinical features. The association of ANCA and disease activity remains controversial; however, the reappearance of ANCA after treatment can indicate a relapse. [ 10 ] [ 11 ]


Although the pathogenic role of ANCA is still controversial,  in vitro  and animal models support the idea that the antibodies have a direct pathological role in the formation of small vessel vasculitides. MPO and PR3 specific ANCA can activate  neutrophils  and  monocytes  through their  Fc  and Fab'2 receptors, which can be enhanced by  cytokines  which cause neutrophils to display MPO and PR3 on their surface. Aberrant glycosylation of the MPO and PR3 specific ANCA enhances their ability to interact with activating Fc receptors on neutrophils. [ 12 ]   The activated neutrophils can then adhere to  endothelial cells  where degranulation occurs. This releases free oxygen radicals and lytic enzymes, resulting in damage to the endothelium via the induction of  necrosis  and  apoptosis . Furthermore, neutrophils release chemoattractive signalling molecules that recruit more neutrophils to the endothelium, acting as a positive feedback loop. Animal models have shown that MPO antibodies can induce necrotizing crescentic glomerulonephritis and systemic small vessel vasculitis. In these animal models the formation of glomerulonephritis and vasculitis can occur in the absence of T-cells, however neutrophils must be present. [ 13 ] [ 14 ] [ 15 ] [ 16 ]  Although ANCA titres have been noted to have limited correlation with disease activity, except for kidney disease, and with risk of relapse, this is explained by differences in the  epitopes  and affinity of ANCAs. [ 17 ]  ANCAs induce excess activation of  neutrophils , resulting in the production of neutrophil extracellular traps (NETs), which cause damage to small blood vessels. [ 17 ]  In addition, in patients with active disease, treated with  Rituximab , an anti- CD20  antibody which remove circulating B-cells, clinical remission  correlates more to the decreasing number of circulating B-cells than decrease in ANCA titre, which in some patient does not change during treatment. The same study found that clinical relapse in some patients were in association with the return of circulating B-cells. [ 18 ]  Based on the above observations and that ANCA reactive  B-cells  can be found in circulation in patients with AAV, an alternative hypothesis have been proposed assigning  a direct pathogenic role of these cells, whereby activated neutrophils and ANCA-reactive B-cells engage in intercellular cross-talk, which leads not only to neutrophil degranulation and inflammation but also to the proliferation and differentiation of ANCA-reactive B-cells. [ 19 ]  However, this hypothesis remains to be tested.


Avacopan  was approved for medical use in the United States to treat anti-neutrophil cytoplasmic autoantibody-associated vasculitis in October 2021. [ 20 ]


ANCAs were originally described in Davies  et al.  in 1982 in  segmental necrotising glomerulonephritis . [ 17 ] [ 21 ]  The Second International ANCA Workshop, held in The Netherlands in May 1989, fixed the nomenclature on perinuclear vs. cytoplasmic patterns, and the antigens MPO and PR3 were discovered in 1988 and 1989, respectively. [ 22 ]  International ANCA Workshops have been carried out every two years. [ citation needed ]


An  anticoagulant , commonly known as a  blood thinner , is a  chemical substance  that prevents or reduces the  coagulation  of  blood , prolonging the  clotting time . [ 1 ]  Some occur naturally in  blood-eating  animals, such as  leeches  and  mosquitoes , which help keep the bite area unclotted long enough for the animal to obtain blood. [ 2 ] [ 3 ]


As a class of  medications , anticoagulants are used in  therapy  for  thrombotic disorders . [ 4 ]   Oral  anticoagulants (OACs) are taken by many people in  pill  or  tablet  form, and various  intravenous  anticoagulant  dosage forms  are used in hospitals. [ 5 ] [ 6 ]  Some anticoagulants are used in medical equipment, such as sample tubes,  blood transfusion  bags,  heart–lung machines , and  dialysis  equipment. [ 7 ] [ 8 ]  One of the first anticoagulants,  warfarin , was initially approved as a  rodenticide . [ 9 ]


Anticoagulants are closely related to  antiplatelet drugs  and  thrombolytic  drugs by manipulating the various pathways of blood coagulation. [ 10 ]  Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit specific pathways of the coagulation cascade, which happens after the initial platelet aggregation but before the formation of fibrin and stable aggregated platelet products. [ 11 ] [ 12 ]


Common anticoagulants include warfarin and  heparin . [ 13 ]


The use of anticoagulants is a decision based on the risks and benefits of anticoagulation. [ 14 ]  The biggest risk of anticoagulation therapy is the increased risk of bleeding. [ 15 ]  In otherwise healthy people, the increased risk of bleeding is minimal, but those who have had recent surgery,  cerebral aneurysms , and other conditions may have too great a risk of bleeding. [ 16 ] [ 17 ]  Generally, the benefit of anticoagulation is preventing or reducing the progression of a thromboembolic disease. [ 18 ]  Some indications for anticoagulant therapy that are known to have benefit from therapy include:


In these cases, anticoagulation therapy  prevents the formation  or growth of dangerous clots. [ 30 ]


The decision to begin therapeutic anticoagulation often involves the use of multiple bleeding risk predictable outcome tools as non-invasive pre-test stratifications due to the potential for bleeding while on blood thinning agents. [ 15 ]  Among these tools are  HAS-BLED , [ 31 ]  ATRIA, [ 32 ]  HEMORR2HAGES, [ 33 ]  and  CHA2DS2-VASc . [ 34 ]  The risk of bleeding using the risk assessment tools above must then be weighed against thrombotic risk to formally determine the patient's overall benefit in starting anticoagulation therapy. [ 35 ]


There is no evidence to indicate that adding anticoagulant therapy to standard treatment has a benefit for people with cerebral small vessel disease but not dementia, and there is an increased risk of a person with this disease experiencing a bleed with this approach. [ 36 ]


The most serious and common adverse side effects associated with anticoagulants are increased risk of bleeding, both nonmajor and major bleeding events. [ 37 ]  The bleeding risk depends on the class of anticoagulant agent used, the patient's age, and pre-existing health conditions. Warfarin has an estimated incidence of bleeding of 15-20% per year and a life-threatening bleeding rate of 1-3% per year. [ 38 ]  Newer non-vitamin K antagonist oral anticoagulants appear to have fewer life-threatening bleeding events than warfarin. [ 39 ] [ 40 ]  Additionally, patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years. [ 41 ]  Bleeding risk is especially important to consider in patients with renal impairment and NOAC therapy because all NOACs, to some extent, are excreted by the kidneys. [ 42 ]  Thus, patients with renal impairment may be at higher risk of increased bleeding. [ 43 ]


In people with cancer, a systematic review has found warfarin had no effect on death rate or the risk of blood clots. [ 44 ]  However, it did increase the risk of major bleeding in 107 more people per 1000 population and minor bleeding in 167 more people per 1000 population. [ 44 ]  Apixaban had no effect on mortality, recurrence of blood clots in blood vessels, or major or minor bleeding. However, this finding comes only from one study. [ 44 ]


Nonhemorrhagic adverse events are less common than hemorrhagic adverse events but should still be monitored closely. [ 39 ]  Nonhemorrhagic adverse events of warfarin  include skin  necrosis , limb gangrene, and purple toe syndrome. [ 45 ]  Skin necrosis and limb gangrene are most commonly observed on the third to eighth day of therapy. [ 46 ] [ 47 ]  The exact pathogenesis of skin necrosis and limb gangrene is not completely understood but it is believed to be associated with warfarin's effect on inhibiting the production of protein C and protein S. [ 48 ] [ 49 ]  Purple toe syndrome typically develops three to eight weeks after initiation of warfarin therapy. [ 50 ] [ 51 ]  Other adverse effects of warfarin are associated with depletion of vitamin K, which can lead to inhibition of G1a proteins and growth arrest-specific gene 6, which can lead to increased risk of arterial calcification and heart valve, especially if too much Vitamin D is present. [ 52 ] [ 53 ]  Warfarin's interference with G1a proteins has also been linked to abnormalities in fetal bone development in mothers who were treated with warfarin during pregnancy. [ 54 ] [ 55 ]  Long-term warfarin and heparin usage have also been linked to osteoporosis. [ 56 ] [ 45 ]


Another potentially severe complication associated with heparin use is called heparin-induced thrombocytopenia (HIT). [ 57 ]  There are two distinct types: HIT 1) immune-mediated and 2) non-immune-mediated. [ 57 ]  Immune-mediated HIT most commonly arises five to ten days after exposure to heparin. [ 58 ]  Pathogenesis of immune-mediated HIT is believed to be caused by heparin-dependent immunoglobulin antibodies binding to platelet factor 4/heparin complexes on platelets, leading to widespread platelet activation. [ 59 ]


Foods and  food supplements  with blood-thinning effects include  nattokinase ,  lumbrokinase ,  beer ,  bilberry ,  celery ,  cranberries ,  fish oil ,  garlic ,  ginger ,  ginkgo ,  ginseng ,  green tea ,  horse chestnut ,  licorice ,  niacin ,  onion ,  papaya ,  pomegranate ,  red clover ,  soybean ,  St. John's wort ,  turmeric ,  wheatgrass , and  willow  bark. [ 60 ] [ 61 ] [ 62 ]  Many herbal supplements have blood-thinning properties, such as  danshen  and  feverfew . [ 63 ]  Multivitamins that do not interact with clotting are available for patients on anticoagulants. [ 64 ]


However, some foods and supplements encourage clotting. [ 65 ]  These include  alfalfa ,  avocado ,  cat's claw ,  coenzyme Q10 , and dark leafy greens such as  spinach . [ 66 ] [ 67 ]  Excessive intake of the food mentioned above should be avoided while taking anticoagulants, or if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability. [ 68 ] [ 69 ]


Grapefruit  interferes with some anticoagulant drugs, increasing the time it takes for them to be metabolized out of the body, and should be eaten with caution when on anticoagulant drugs. [ 70 ]


Anticoagulants are often used to treat acute  deep-vein thrombosis . [ 71 ] [ 72 ]  People using anticoagulants to treat this condition should avoid using  bed rest  as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way. [ 73 ]  Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary. [ 73 ]


Several anticoagulants are available. Warfarin, other coumarins, and heparins have long been used. [ 74 ]  Since the 2000s, several agents have been introduced that are collectively referred to as  direct oral anticoagulants  ( DOACs ), previously named  novel oral anticoagulants  ( NOACs ) or  non-vitamin K antagonist oral anticoagulants . [ 75 ] [ 76 ] [ 77 ] [ 78 ]  These agents include direct thrombin inhibitor ( dabigatran ) and factor Xa inhibitor ( rivaroxaban ,  apixaban ,  betrixaban  and  edoxaban ), and they have been shown to be as good or possibly better than the coumarins with less serious side effects. [ 79 ]  The newer anticoagulants (NOACs/DOACs) are more expensive than the traditional ones and should be used in caring for patients with kidney problems. [ 80 ]


These oral anticoagulants are derived from  coumarin  found in many plants. A prominent member of this class,  warfarin  (Coumadin), was found to be the anticoagulant most prescribed in a large multispecialty practice. [ 81 ]  The anticoagulant effect takes at least 48 to 72 hours to develop. Where an immediate effect is required,  heparin  is given concomitantly. These anticoagulants are used to treat patients with  deep-vein thrombosis  (DVT) and  pulmonary embolism  (PE) and to prevent emboli in patients with  atrial fibrillation  (AF), and mechanical  prosthetic heart valves . Other examples are  acenocoumarol ,  phenprocoumon ,  atromentin , and  phenindione . [ citation needed ]


The coumarins  brodifacoum  and  difenacoum  are used as mammalicides (particularly as  rodenticides ) but are not used medically. [ citation needed ]


Heparin is the most widely used intravenous clinical anticoagulant worldwide. [ 82 ]   Heparin  is a naturally occurring  glycosaminoglycan . There are three major categories of heparin: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and ultra-low-molecular weight heparin (ULMWH). [ 83 ]   Unfractionated heparin is usually derived from  pig  intestines and bovine lungs. [ 84 ]  UFH binds to the enzyme inhibitor  antithrombin  III (AT), causing a conformational change that results in its activation. [ 85 ]  The activated AT then inactivates  factor Xa ,  thrombin , and other coagulation factors. [ 86 ]  Heparin can be used  in vivo  (by injection), and also  in vitro  to prevent blood or plasma clotting in or on medical devices. In  venipuncture ,  Vacutainer  brand blood collecting tubes containing heparin usually have a green cap. [ 87 ]


Low molecular weight heparin  (LMWH) is produced through a controlled depolymerization of unfractionated heparin. [ 83 ]  LMWH exhibits a higher anti-Xa/anti-IIa activity ratio and is useful as it does not require monitoring of the  APTT   coagulation  parameter and has fewer side effects. [ 83 ]


The direct oral anticoagulants (DOACs) were introduced in and after 2008. [ 88 ]  There are five DOACs currently on the market:  dabigatran ,  rivaroxaban ,  apixaban ,  edoxaban  and  betrixaban . [ 89 ]  They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs). [ 90 ]


Compared to warfarin, DOACs have a rapid onset action and relatively short half-lives; hence, they carry out their function more rapidly and effectively, allowing drugs to reduce their anticoagulation effects quickly. [ 91 ]   Routine monitoring and dose adjustments of DOACs are less important than for warfarin, as they have better predictable anticoagulation activity. [ 92 ]  DOAC monitoring, including laboratory monitoring and a complete medication review, should generally be conducted before initiation of a DOAC, 1–3 months after initiation, and then every 6–12 months afterwards. [ 93 ]


Both DOACs and warfarin are equivalently effective, but compared to warfarin, DOACs have fewer drug interactions, no known dietary interactions, a wider therapeutic index, and have conventional dosing that does not require dose adjustments with constant monitoring. [ 94 ] [ 92 ]  However, there is no countermeasure for most DOACs, unlike for warfarin; nonetheless, the short half-lives of DOACs will allow their effects to recede swiftly. A reversal agent for dabigatran,  idarucizumab , is currently available and approved for use by the FDA. Rates of adherence to DOACs are only modestly higher than adherence to warfarin among patients prescribed these drugs. Thus, adherence to anticoagulation is often poor despite hopes that DOACs would lead to higher adherence rates. [ 95 ]


DOACs are significantly more expensive than warfarin, but the patients on DOACs may experience reduced lab costs as they do not need to monitor their INR. [ 93 ]


Drugs such as  rivaroxaban ,  apixaban  and  edoxaban  work by inhibiting factor Xa directly (unlike heparins and fondaparinux, which work via antithrombin activation).
Also included in this category are  betrixaban  from Portola Pharmaceuticals, the discontinued  darexaban  (YM150) from Astellas, and, more recently,  the discontinued  letaxaban  (TAK-442) from Takeda and  eribaxaban  (PD0348292) from Pfizer.
Betrixaban is significant as it was in 2018, the only oral factor Xa inhibitor approved by the FDA for use in acutely medically ill patients. [ 96 ]  Darexaban development was discontinued in September 2011; in a trial for prevention of recurrences of myocardial infarction in addition to dual antiplatelet therapy (DAPT), the drug did not demonstrate effectiveness, and the risk of bleeding was increased by approximately 300%. [ 97 ]  The development of letaxaban for acute coronary syndrome was discontinued in May 2011 following negative results from a Phase II study. [ 98 ]


Another type of anticoagulant is the  direct thrombin inhibitor . [ 99 ]  Current members of this class include the bivalent drugs  hirudin ,  lepirudin , and  bivalirudin  and the monovalent drugs  argatroban  and  dabigatran . An oral direct thrombin inhibitor,  ximelagatran  (Exanta), was denied approval by the  Food and Drug Administration  (FDA) in September 2004 [ 100 ]  and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. [ 101 ]  In November 2010,  dabigatran etexilate  was approved by the FDA to prevent thrombosis in  atrial fibrillation .


As in any invasive procedure, patients on anticoagulation therapy have an increased risk for bleeding, and caution should be used along with local  hemostatic  methods to minimize bleeding risk during the operation as well as postoperatively. [ 102 ]  However, with regards to DOACs and invasive dental treatments, there has not been enough clinical evidence and experience to prove any reliable adverse effects, relevance or interaction between these two. [ 103 ]  Further clinical prospective studies on DOACs are required to investigate the bleeding risk and hemostasis associated with surgical and dental procedures. [ 104 ]


Recommendations of modifications to the usage/dosage of DOACs before dental treatments are made based on the balance of the bleeding risk of each procedure and also the individual's own bleeding risks and renal functionality. [ 105 ]  With low-bleeding-risk dental procedures, it is recommended that DOACs be continued by the patient to avoid any increase in the risk of a thromboembolic event. [ 106 ] [ 107 ]  For dental procedures with a higher risk of bleeding complications (i.e. complex extractions, adjacent extractions leading to a large wound, or more than three extractions), the recommended practice is for the patient to miss or delay a dose of their DOAC before such procedures to minimize the effect on bleeding risk. [ 108 ]


The antithrombin protein is used as a  protein therapeutic  that can be purified from human plasma [ 109 ]  or produced recombinantly (for example, Atryn, produced in the milk of  genetically modified  goats). [ 110 ] [ 111 ]


The FDA approves Antithrombin as an anticoagulant for preventing clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency. [ 109 ] [ 111 ]


Many other anticoagulants exist in  research and development ,  diagnostics , or as drug candidates.


With the growing number of patients taking oral anticoagulation therapy, studies into reversal agents are gaining increasing interest due to major bleeding events and the need for urgent anticoagulant reversal therapy. [ 112 ]  Reversal agents for warfarin are more widely studied, and established guidelines for reversal exist due to a longer history of use of warfarin and the ability to get a more accurate measurement of anticoagulation effect in a patient via measuring the INR (International Normalized Ratio). [ 113 ]  In general, vitamin K is most commonly used to reverse the effect of warfarin in non-urgent settings. [ 114 ]  However, in urgent settings or settings with extremely high INR (INR >20), hemostatic reversal agents such as fresh frozen plasma (FFP),  recombinant factor VIIa , and prothrombin complex concentrate (PCC) have been utilized with proven efficacy. [ 115 ]  Specifically with warfarin, four-factor PCC (4F-PCC) has been shown to have superior safety and mortality benefits compared to FPP in lowering INR levels. [ 112 ]


Although specific antidotes and reversal agents for DOACs are not as widely studied,  idarucizumab  (for dabigatran) and  andexanet alfa  (for factor Xa inhibitor) have been used in clinical settings with varying efficacy. [ 90 ]   Idarucizumab is a monoclonal antibody, approved by the US FDA in 2015, that reverses the effect of dabigatran by binding to both free and thrombin-bound dabigatran. [ 116 ] [ 117 ]  Andexanet alfa is a recombinant modified human factor Xa decoy that reverses the effect of factor Xa inhibitors by binding at the active sites of factor Xa inhibitor and making it catalytically inactive. [ 118 ] [ 119 ]  Andexanet alfa was approved by the US FDA in 2018. [ 120 ]  Another drug called ciraparantag, a potential reversal agent for direct factor Xa inhibitors, is still under investigation. [ 121 ]  Additionally, hemostatic reversal agents have also been used with varying efficacy to reverse the effects of DOACs. [ 122 ] [ 123 ]


A  Bethesda unit  ( BU ) is a measure of blood  coagulation inhibitor  activity. It is the amount of inhibitor that will inactivate half of a  coagulant  during the incubation period. [ 124 ]  It is the standard measure used in the United States and is so named because it was adopted as a standard at a conference in  Bethesda, Maryland . [ 125 ]


If blood is allowed to clot,  laboratory  instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and non-operational. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Besides heparin, most of these chemicals  bind   calcium  ions, preventing the coagulation proteins from using them.


Dental practitioners play an important role in the early detection of anticoagulant overdose through oral manifestations, as the patient does not show any symptoms. Dental treatment of patients taking anticoagulant or antiplatelet medication raises safety concerns in terms of the potential risk of bleeding complications following invasive dental procedures. Therefore, certain guidelines for the dental care of patients taking these drugs are needed.


Detecting overdose


An overdose of anticoagulants usually occurs in people who have heart problems and need to take anticoagulants in the long term to reduce the risk of stroke from their high blood pressure.


An  International Normalised Ratio (INR)  test would be recommended to confirm the overdose so that the dosage can be adjusted to an acceptable standard. The INR test measures the time it takes for a clot to form in a blood sample relative to a standard.


An INR value of 1 indicates a level of coagulation equivalent to that of an average patient not taking warfarin, and values greater than 1 indicate a longer clotting time and, thus, a longer bleeding time.


Assessing bleeding risk


There are two main parts to the assessment of bleeding risk:


Managing bleeding risk


A patient who is on anticoagulants or  antiplatelet  medications may undergo dental treatments which are unlikely to cause bleeding, such as local anesthesia injection, basic gum charting, removal of plaque, calculus and stain above the gum level, direct or indirect fillings which are above the gingiva,  root canal treatment , taking impression for denture or crown and fitting or adjustment of  orthodontic appliances .  For all these procedures, it is recommended that the dentist treat the patient following the normal standard procedure and taking care to avoid any bleeding.


For a patient who needs to undergo dental treatments which are more likely to cause bleeding, such as simple tooth extractions (1-3 teeth with small wound size), drainage of swelling inside the mouth, periodontal charting,  root planing ,  direct or indirect filling which extends below the gingiva, complex filling, flap raising procedure, gingival recontouring and biopsies, the dentist needs to take extra precautions apart from the standard procedure. The recommendations [ 127 ]  are as follows:


There is general agreement that in most cases, treatment regimens with older anticoagulants (e.g., warfarin) and antiplatelet agents (e.g.,  clopidogrel ,  ticlopidine ,  prasugrel ,  ticagrelor , and/or aspirin) should not be altered before dental procedures. The risks of stopping or reducing these medication regimens (i.e.,  thromboembolism ,  stroke ,  myocardial infarction ) far outweigh the consequences of prolonged bleeding, which can be controlled with local measures. In patients with other existing medical conditions that can increase the risk of prolonged bleeding after dental treatment or receiving other therapy that can increase bleeding risk, dental practitioners may wish to consult the patient's physician to determine whether care can safely be delivered in a primary care office. Any suggested modification to the medication regimen before dental surgery should be done in consultation and on the advice of the patient's physician.


Based on limited evidence, the consensus appears to be that in most patients who are receiving the newer direct-acting oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban, or edoxaban) and undergoing dental treatment (in conjunction with usual local measures to control bleeding), no change to the anticoagulant regimen is required. In patients deemed to be at higher risk of bleeding (e.g., patients with other medical conditions or undergoing more extensive procedures associated with higher bleeding risk), consideration may be given, in consultation with and on advice of the patient's physician, to postponing the timing of the daily dose of the anticoagulant until after the procedure; timing the dental intervention as late as possible after last dose of anticoagulant; or temporarily interrupting drug therapy for 24 to 48 hours.


A substantial number of compounds are being investigated for use as anticoagulants. The most promising ones act on the  contact activation system  ( factor XIIa  and  factor XIa ); it is anticipated that this may provide agents that prevent thrombosis without conferring a risk of bleeding. [ 128 ]


As of November 2021 [update] , the direct factor XIa inhibitor  milvexian  is in Phase II clinical trials for the prevention of an embolism after surgery. [ 129 ]


The  alkali denaturation test , also known as  A  or  Apt test , is a medical test used to differentiate fetal or  neonatal  blood from maternal blood found in a newborn's stool or vomit,  or from maternal vaginal blood. [ 1 ] [ 2 ]


The test was developed by  Leonard Apt  (1922–2013), [ 3 ]  an American pediatric ophthalmologist. The test was originally used to identify the source of bloody stools in newborn infants. It has been modified to distinguish fetal from maternal hemoglobin in blood samples from any source. [ 4 ]


It is used to differentiate whether the blood coming out of vagina is of the mother or fetus during delivery i.e, placenta previa versus vasa previa. It is based on the principle that fetal HbF is resistant to acids and alkali whereas the mother's blood which has HbA is sensitive to acid and alkaline.


The test is based on differences between maternal and fetal  hemoglobin . Maternal blood contains adult hemoglobin composed of two alpha and two beta subunits (aka hemoglobin A or HbA; i.e., normal adult hemoglobin). Fetal blood contains fetal hemoglobin composed of two alpha and two gamma subunits (aka hemoglobin F or HbF; i.e., normal fetal hemoglobin). This difference in composition gives the different types of hemoglobin different chemical properties (in addition to the higher affinity HbF has for dissolved blood oxygen over HbA, allowing baby to extract oxygen from the mother's blood). Fetal hemoglobin is resistant to alkali (basic) denaturation, whereas adult hemoglobin is susceptible to such denaturation. Therefore, exposing the blood specimen to sodium hydroxide ( NaOH ) will denature the adult but not the fetal hemoglobin. The fetal hemoglobin will appear as a pinkish color under the microscope while the adult hemoglobin will appear as a yellow-brownish color.


The blood is mixed with a small amount of sterile water to cause  hemolysis  of the  RBCs , yielding free  hemoglobin . The sample is next centrifuged for several minutes. The pink hemoglobin-containing supernatant is then mixed with 1 mL of 1%  NaOH  for each 5 mL of supernatant. The color of the fluid is assessed after 2 minutes. Fetal hemoglobin will stay pink and adult hemoglobin will turn yellow-brown since adult hemoglobin is less stable and will convert to  hematin  which has a hydroxide ligand. [ 5 ]


The  Arneth count  or  Arneth index  describes the  nucleus  of a type of  white blood cell  called a  neutrophil  in an attempt to detect disease.


Neutrophils  typically have two or three lobes. In general, older neutrophils have more lobes than younger neutrophils. The Arneth count determines the percentage of neutrophils with one, two, three, four, and five or more lobes. [ citation needed ]


The Arneth count is not commonly used in modern medicine.


It is named for  Josef Arneth . [ 1 ] [ 2 ] [ 3 ]


An  arterial blood gas  ( ABG )  test , or  arterial blood gas analysis  ( ABGA ) measures the amounts of arterial gases, such as  oxygen  and  carbon dioxide . An ABG test requires that a small volume of blood be drawn from the  radial artery  with a  syringe  and a thin  needle , [ 1 ]  but sometimes the  femoral artery  in the  groin  or another site is used. The blood can also be drawn from an  arterial catheter .


An ABG test measures the  blood gas tension  values of the  arterial partial pressure of oxygen  (PaO2), and the  arterial partial pressure of carbon dioxide  (PaCO2), and the  blood's pH . In addition, the arterial  oxygen saturation  (SaO2) can be determined. Such information is vital when caring for patients with critical illnesses or respiratory disease. Therefore, the ABG test is one of the most common tests performed on patients in  intensive-care units . In other  levels of care ,  pulse oximetry  plus transcutaneous carbon-dioxide measurement is a less invasive, alternative method of obtaining similar information. [ citation needed ]


An ABG test can indirectly measure the level of  bicarbonate  in the blood.  The bicarbonate level is calculated using the Henderson-Hasselbalch equation. Many blood-gas analyzers will also report concentrations of  lactate ,  hemoglobin , several  electrolytes ,  oxyhemoglobin ,  carboxyhemoglobin , and  methemoglobin . ABG testing is mainly used in  pulmonology  and critical-care medicine to determine  gas exchange  across the alveolar-capillary membrane.  ABG testing also has a variety of applications in other areas of medicine. Combinations of disorders can be complex and difficult to interpret, so calculators, [ 2 ]   nomograms , and rules of thumb [ 3 ]  are commonly used.


ABG  samples  originally were sent from the clinic to the  medical laboratory  for analysis. Newer equipment lets the analysis be done also as  point-of-care testing , depending on the equipment available in each clinic.


Arterial blood for  blood-gas analysis  is usually drawn by a  respiratory therapist  and sometimes a  phlebotomist , a  nurse , a  paramedic  or a doctor. [ 4 ]  Blood is most commonly drawn from the  radial artery  because it is easily accessible, can be compressed to control bleeding, and has less risk for  vascular occlusion . The selection of which radial artery to draw from is based on the outcome of an  Allen's test . The  brachial artery  (or less often, the  femoral artery ) is also used, especially during emergency situations or with children. Blood can also be taken from an arterial catheter already placed in one of these arteries. [ 5 ]


There are plastic and glass syringes used for blood gas samples. [ 6 ]   Most syringes come pre-packaged and contain a small amount of  heparin , to prevent  coagulation . Other syringes may need to be heparinised, by drawing up a small amount of liquid heparin and squirting it out again to remove air bubbles. Once the sample is obtained, [ 7 ]  care is taken to eliminate visible gas bubbles, as these bubbles can dissolve into the sample and cause inaccurate results.  The sealed syringe is taken to a  blood gas analyzer . [ 8 ]   If a plastic blood gas syringe is used, the sample should be transported and kept at room temperature and analyzed within 30 min.  If prolonged time delays are expected (i.e., greater than 30 min) prior to analysis, the sample should be drawn in a glass syringe and immediately placed on ice. [ 9 ]   Standard blood tests can also be performed on arterial blood, such as measuring  glucose ,  lactate ,  hemoglobins , dyshemoglobins,  bilirubin  and   electrolytes . [ citation needed ]


Derived parameters include bicarbonate concentration, SaO2, and base excess.  Bicarbonate concentration is calculated from the measured pH and PCO2 using the Henderson-Hasselbalch equation.  SaO2 is derived from the measured PO2 and calculated based on the assumption that all measured hemoglobin is normal (oxy- or deoxy-) hemoglobin. [ 10 ]


The machine used for analysis aspirates this blood from the syringe and measures the  pH  and the  partial pressures  of oxygen and carbon dioxide. The bicarbonate concentration is also calculated. These results are usually available for interpretation within five minutes. [ citation needed ]


Two methods have been used in medicine in the management of blood gases  of patients in  hypothermia : pH-stat method and alpha-stat method. Recent studies suggest that the α-stat method is superior. [ citation needed ]


Both the pH-stat and alpha-stat strategies have theoretical disadvantages. α-stat method is the method of choice for optimal myocardial function. The pH-stat method may result in loss of autoregulation in the brain (coupling of the cerebral blood flow with the metabolic rate in the brain). By increasing the cerebral blood flow beyond the metabolic requirements, the pH-stat method may lead to cerebral microembolisation and intracranial hypertension. [ 10 ]


These are typical  reference ranges , although various analysers and laboratories may employ different ranges.


There are two calculations for base excess (extra cellular fluid - BE(ecf); blood - BE(b)).  The calculation used for the BE(ecf) = [ HCO − 3 ]− 24.8 + 16.2 × (pH − 7.4). The calculation used for BE(b) = (1 − 0.014 ×  Hgb ) × ([ HCO − 3 ]− 24.8 + (1.43 × Hgb + 7.7) × (pH − 7.4).


Contamination of the sample with room air will result in abnormally low carbon dioxide and possibly elevated oxygen levels, and a concurrent elevation in pH.  Delaying analysis (without chilling the sample) may result in inaccurately low oxygen and high carbon dioxide levels as a result of ongoing cellular respiration.


The normal range for pH is 7.35–7.45. As the pH decreases (< 7.35), it implies  acidosis , while if the pH increases (> 7.45) it implies  alkalosis . In the context of arterial blood gases, the most common occurrence will be that of  respiratory acidosis .  Carbon dioxide is dissolved in the blood as carbonic acid, a weak acid; however, in large concentrations, it can affect the pH drastically. Whenever there is poor pulmonary ventilation, the carbon dioxide levels in the blood are expected to rise. This leads to a rise of carbonic acid, leading to a decrease in pH. The first buffer of pH will be the plasma proteins, since these can accept some H +  ions to try to maintain  acid-base homeostasis . As carbon dioxide concentrations continue to increase ( Pa CO 2  > 45 mmHg), a condition known as respiratory acidosis occurs. The body tries to maintain homeostasis by increasing the respiratory rate, a condition known as tachypnea. This allows much more carbon dioxide to escape the body through the lungs, thus increasing the pH by having less carbonic acid. If a person is in a critical setting and intubated, one must increase the number of breaths mechanically. [ citation needed ]


Respiratory alkalosis  ( Pa  CO 2  < 35 mmHg) occurs when there is too little carbon dioxide in the blood. This may be due to hyperventilation or else excessive breaths given via a  mechanical ventilator  in a critical care setting. The action to be taken is to calm the person and try to reduce the number of breaths being taken to normalize the pH. The respiratory pathway tries to compensate for the change in pH in a matter of 2–4 hours. If this is not enough, the metabolic pathway takes place. [ citation needed ]


Under normal conditions, the  Henderson–Hasselbalch equation  will give the blood pH


where:


The kidney and the liver are two main organs responsible for the metabolic homeostasis of pH. Bicarbonate is a base that helps to accept excess hydrogen ions whenever there is acidaemia. However, this mechanism is slower than the respiratory pathway and may take from a few hours to 3 days to take effect. In acidaemia, the bicarbonate levels rise, so that they can neutralize the excess acid, while the contrary happens when there is alkalaemia. Thus when an arterial blood gas test reveals, for example, an elevated bicarbonate, the problem has been present for a couple of days, and metabolic compensation took place over a blood acidaemia problem. [ citation needed ]


In general, it is much easier to correct acute pH derangement by adjusting respiration. Metabolic compensations take place at a much later stage. However, in a critical setting, a person with a normal pH, a high CO 2 , and a high bicarbonate means that, although there is a high carbon dioxide level, there is metabolic compensation. As a result, one must be careful as to not artificially adjust breaths to lower the carbon dioxide. In such case, lowering the carbon dioxide abruptly means that the bicarbonate will be in excess and will cause a metabolic alkalosis. In such a case, carbon dioxide levels should be slowly diminished. [ citation needed ]


Since the advent of  pulse oximetry  which measures oxygen saturation transcutaneously and is non-invasive, arterial blood is seldom used for the determination of oxygenation outside the ICU. Acid base status can be determined with  venous blood   precluding the pain and inconvenience of arterial blood sampling in most cases. When an indwelling arterial line  catheter  is present, arterial blood is easy to obtain and still used.  Venous blood  is generally used otherwise, usually from a   peripheral   vein, such as a forearm vein.
The values of pH and HCO3 of venous blood are close enough to arterial blood for direct comparison. The pCO2 of  venous blood  is less reliably compared to arterial blood but may be used in some cases. The PO2 level of venous blood is always significantly lower that arterial and should be reported, labeled and interpreted as venous PO2.
 [ 21 ]


A  basic metabolic panel  ( BMP )  is a blood test consisting of a set of seven or eight biochemical tests and is one of the most common lab tests ordered by health care providers. Outside the  United States , blood tests made up of the majority of the same biochemical tests are called  urea and electrolytes  ( U&E  or " U and Es "), or  urea, electrolytes, creatinine  ( UEC  or  EUC  or  CUE ), and are often referred to as 'kidney function tests' as they also include a calculated estimated  glomerular filtration rate . The BMP provides key information regarding fluid and electrolyte status, kidney function, blood sugar levels, and response to various medications and other medical therapies. It is frequently employed as a screening tool during a  physical exam .


The basic metabolic panel is a simpler version of the  comprehensive metabolic panel  (CMP), which includes tests for liver function.


The version with seven tests is often referred to by medical professionals in the United States as the "CHEM-7", or "SMA-7" (Sequential Multiple Analysis-7). [ 1 ]


The seven parts of a CHEM-7 are tests for:


These levels, taken as a set, can be rapidly performed to indicate several common acute conditions requiring immediate specific medical treatment, such as  dehydration / hypovolemia ,  water intoxication  (which can present with similar symptoms to dehydration but requires the opposite treatment),  diabetic shock  (either  ketoacidosis ,  hyperglycemia  or  hypoglycemia ),  congestive heart failure ,  kidney failure  or  liver failure , various substance overdoses or adverse reactions, and others. A Chem-7 is thus a vital tool when attempting to stabilize a patient. [ citation needed ]


Calcium  (Ca 2+ ) is often considered part of the BMP, [ 9 ] [ 10 ]  though, by definition, it is not part of the CHEM-7. A basic metabolic panel including calcium is sometimes colloquially referred to as a "CHEM-8". Calcium, as an  alkaline earth metal , is also an electrolyte, but abnormalities are more commonly associated with malnutrition,  osteoporosis , or  malignancy , especially of the  thyroid . [ citation needed ]


In countries that do not use the CHEM-7 panel, a UEC typically does not include chloride or bicarbonate as standard components, but will often include an  estimated glomerular filtration rate  (eGFR), and in some laboratories, glucose is also not included but is available as a separate test.


The results of a basic metabolic panel are traditionally represented in a standard grid:


Glucose (and sometimes calcium,  magnesium , and  phosphorus ) are listed to the right of this grid, but there is greater variation in how these values are reported. [ citation needed ]


The  Beutler test , also known as the  fluorescent spot test , [ 1 ]  is a  screening  test used to identify enzyme defects. [ 2 ] [ 3 ] [ 4 ]


It can be used in screening for:


The  biological terrain assessment  or  BTA  is a set of tests used to measure the  pH ,  resistivity , and  redox  of a person's  urine ,  blood , and  saliva . [ 1 ] [ 2 ]  The measurements were first used by L.C. Vincent, a  French   hydrologist , in the early 1900s. [ 3 ]  It is often associated with  homeopathy  and  holistic health . The usefulness of the test is debatable and according to physician  Stephen Barrett  BTA is outdated, apart from pH measurement, and is an inferior assessment technique that should not be favored over more modern techniques. [ 1 ]


Proponents of the BTA claim that comparing the pH, resistivity, and  redox  of the blood, urine, and saliva provides a health practitioner an indication of the metabolic processes taking place inside the body. [ 2 ]  There is no scientific evidence that these measurements provide a medically relevant indication of metabolic processes. Multiple manufacturers of BTA equipment have been prevented from selling their equipment in the United States because they lack  Food and Drug Administration  (FDA) approval. However, the FDA has not stated whether the BTA is medically useful or not. [ citation needed ]


The Quantitative Fluid Analyzer (QFA) manufactured by Health Science Company does have FDA classification as a "laboratory instrument for medical purposes" "ion selective", Class 1 510(K) exempt. [ citation needed ]  However it does not have CLIA (Clinical Laboratory improvement Amendment, 1988) waiver. [ citation needed ]


This article about  alternative medicine  is a  stub . You can help Wikipedia by  expanding it .


Birchfield v. North Dakota , 579 U.S. 438 (2016) is a case in which the  Supreme Court of the United States  held that the  search incident to arrest  doctrine permits law enforcement to conduct warrantless breath tests but not blood tests on suspected drunk drivers. [ 1 ]


Birchfield  was a consolidation of three cases:  Birchfield v. North Dakota ,  Bernard v. Minnesota , and  Beylund v. Levi . Birchfield was charged with violation of a North Dakota statute for refusing to submit to blood alcohol content testing; Bernard was charged with a violation of a Minnesota statute for refusing to submit to breath alcohol testing; Beylund underwent a blood alcohol test consistent with North Dakota's  implied consent  law and challenged the constitutionality of that law after an administrative hearing based on the test results led to the revocation of his license.


In  Missouri v. McNeely , 569 U.S. 141 (2013), the Court held that in the absence of an argument based on facts specific to the case "the natural dissipation of alcohol from the bloodstream does not  always  constitute an  exigency  justifying the warrantless taking of a blood sample". In contrast to the court's 1966 finding in  Schmerber v. California , 384 U. S. 757  [ 2 ]  held that the same exigent circumstance did exist by inferring that an officer might reasonably believe it to exist. The court "did not address any potential justification for warrantless testing of drunk driving suspects, except for the exception 'at issue in the case,' namely, the exception for exigent circumstances". [ 3 ]


The issue before the court was how the "search incident to arrest doctrine applies to breath and blood tests". Is warrantless alcohol testing incident to drunk driving arrests to determine  blood alcohol content  a violation of the  Fourth Amendment ?


The Court held that both breath tests and blood tests constitute a search under the Fourth Amendment. The Court then proceeded to analyze both types of tests under the search incident to arrest doctrine, weighing on the one hand "the degree to which it intrudes upon an individual’s privacy" and on the other hand "the degree to which it is needed for the promotion of legitimate governmental interests." Applied to breath tests, the Court concluded that breath tests do not implicate significant privacy concerns. Blood tests, on the other hand, are significantly more intrusive. Turning to the government's interest in the tests, the Court concluded that serves the very important function of providing an incentive to cooperate in alcohol testing. Weighing these interests, the Court concluded that requiring breath tests is constitutional; however, requiring blood tests is not, as the goal of traffic safety can be obtained by less invasive means (such as breath tests).


In the majority opinion, in addressing the limits of implied consent laws, the court stated that while their "prior opinions have referred approvingly to the general concept of implied-consent laws" that "there must be a limit to the consequences to which motorists may be deemed to have consented by virtue of a decision to drive on public roads" and "that motorists could be deemed to have consented to only those conditions that are 'reasonable' in that they have a 'nexus' to the privilege of driving".


The Court ruled in favor of Birchfield who was prosecuted for refusing a warrantless blood draw and ruled against Bernard who refused a warrantless breath test.  Beylund, on the other hand consented to a blood test after police advised him that he was required to do.  The court therefore remanded Beylund's case back to the state court "to reevaluate Beylund's consent given the partial inaccuracy of the officer's advisory." The Supreme Court of North Dakota court subsequently avoided the issue by holding that, even assuming the consent was involuntary, the Exclusionary Rule does not apply in the administrative hearing context and thus affirmed suspension of his license for testing over the prohibited level set forth in the implied consent / administrative license suspension statute. [ 4 ]


Justice Clarence Thomas wrote that "the search-incident-to-arrest exception to the Fourth Amendment’s warrant requirement should apply categorically to all blood alcohol tests, including  blood tests . By drawing an arbitrary line between blood tests and  breath tests , the majority destabilized the law of exceptions to the warrant requirement and made the jobs of both police officers and lower courts more difficult." [ 5 ]  The Supreme Court ruled in favor of Birchfield in a 7–1 majority stating that the refusal to submit to a warrantless blood test may not be criminalized as it is a violation of the petitioner's  Fourth Amendment right against unlawful searches  and is protected by neither the  search incident to arrest  nor  exigent circumstances  exceptions of the Fourth Amendment's warrant requirement. The Supreme Court also stated that the same rationale applied to the decision of warrantless breath tests was not relevant based on the implication of serious privacy concerns brought about by the administration of blood tests which could be used to obtain information other than the  BAC  of the suspected drunk driver as well as the intrusive process used to obtain a blood sample.


Justice Sonia Sotomayor wrote that "the Fourth Amendment’s prohibition against warrantless searches should apply to breath tests unless exigent circumstances justify one in a particular case. In establishing exceptions to the warrant requirement, the Court has routinely examined whether a legitimate government interest justified the search in light of the individual’s privacy interest and whether that determination should be made based on a case-by-case analysis or a categorical rule." [ 5 ]  Justice Sotomayor argued that the administration of a warrantless breath test was not imperative to the prevention of drunk drivers as the suspected drunk driver has already been removed from the roadway and a search warrant could be obtained if necessary. The Supreme Court ruled 6–2 in favor of The State of North Dakota stating that warrantless breath tests are protected under the search incident to arrest warrant exception of the Fourth Amendment's warrant requirement and require minimal physical intrusion. The Supreme Court majority also argued that the administration of a warrantless breath tests serves the government's objectives of deterring drunk drivers as well as effectively allowing law enforcement officers to remove already present drunk drivers from the roadways.


Bleeding time  is a  medical test  done to assess the function of a person's  platelets . It involves making a patient bleed, then timing how long it takes for them to stop bleeding using a  stopwatch  or other suitable devices.


The term  template bleeding time  is used when the test is performed to standardized parameters.


A newer alternative to the traditional bleeding time test is the platelet function screen performed on the PFA-100 analyzer. [ 1 ]


The template bleeding time test is a method used when other more reliable and less invasive tests for determining  coagulation  are not available. [ 2 ]  Historically, it was used whenever physicians needed information about platelet activation. [ 3 ]


The test involves cutting the underside of the subject's forearm, in an area where there is no hair or visible  veins . The cut is of a standardized width and depth, and is done quickly by a template device. [ 4 ]


The IVY method is the traditional format for this test. While both the IVY and Duke's method require the use of a  sphygmomanometer , or blood pressure cuff, the IVY method is more invasive than the Duke method, utilizing an  incision  on the ventral side of the forearm, whereas the Duke method involves puncture with a  lancet  or special needle.  In the IVY method, the blood pressure cuff is placed on the upper arm and inflated to 40 mmHg. A lancet or scalpel blade is used to make a shallow incision that is 1 millimeter deep on the underside of the forearm. [ 5 ]


A standard-sized incision is made around 10 mm long and 1 mm deep. The time from when the incision is made until all bleeding has stopped is measured and is called the bleeding time. Every 30 seconds, filter paper or a paper towel is used to draw off the blood.


The test is finished when bleeding has stopped. [ 6 ]


A prolonged bleeding time may be a result from decreased number of thrombocytes or impaired blood vessels. However, the depth of the puncture or incision may be the source of error.


Normal values  fall between 3 – 10 minutes depending on the method used.