Thrombosis prevention is initiated with assessing the risk for its development.  Some people have a higher risk  of developing thrombosis and its possible development into  thromboembolism . [ 16 ]  Some of these risk factors are related to  inflammation .


" Virchow's triad " has been suggested to describe the three factors necessary for the formation of thrombosis:


Some risk factors predispose for venous thrombosis while others increase the risk of arterial thrombosis. [ citation needed ]  Newborn babies in the neonatal period are also at risk of a thromboembolism. [ 19 ]


The main causes of thrombosis are given in  Virchow's triad  which lists  thrombophilia ,  endothelial cell  injury, and disturbed  blood flow . Generally speaking the risk for thrombosis increases over the life course of individuals, depending on life style factors like smoking, diet, and physical activity, the presence of other diseases like cancer or autoimmune disease, while also platelet properties change in aging individuals which is an important consideration as well. [ 31 ]


Hypercoagulability or  thrombophilia , is caused by, for example,  genetic deficiencies  or  autoimmune disorders . Recent studies indicate that white blood cells play a pivotal role in deep vein thrombosis, mediating numerous pro-thrombotic actions. [ 32 ]


Any inflammatory process, such as trauma, surgery or infection, can cause damage to the  endothelial lining  of the vessel's wall. The main mechanism is exposure of  tissue factor  to the blood coagulation system. [ 33 ]  Inflammatory and other stimuli (such as  hypercholesterolemia ) can lead to changes in  gene expression  in endothelium producing to a pro-thrombotic state. [ 34 ]  When this occurs, endothelial cells  downregulate  substances such as  thrombomodulin , which is a key modulator of thrombin activity. [ 35 ]  The result is a sustained activation of thrombin and reduced production of  protein C  and tissue factor inhibitor, which furthers the pro-thrombotic state. [ 34 ]


Endothelial injury is almost invariably involved in the formation of thrombi in arteries, as high rates of blood flow normally hinder clot formation. In addition, arterial and cardiac clots are normally rich in platelets–which are required for clot formation in areas under high stress due to blood flow. [ 34 ]


Causes of disturbed blood flow include stagnation of blood flow past the point of injury, or  venous stasis  which may occur in heart failure, [ 33 ]  or after long periods of sedentary behaviour, such as sitting on a long airplane flight. Also,  atrial fibrillation , causes stagnant blood in the left atrium (LA), or  left atrial appendage  (LAA), and can lead to a  thromboembolism . [ 33 ]   Cancers  or  malignancies  such as  leukemia  may cause increased risk of thrombosis by possible activation of the coagulation system by cancer cells or secretion of procoagulant substances ( paraneoplastic syndrome ), by external compression on a blood vessel when a solid tumor is present, or (more rarely) extension into the vasculature (for example, renal cell cancers extending into the renal veins). [ 33 ]  Also, treatments for cancer (radiation, chemotherapy) often cause additional hypercoagulability. [ 33 ]  There are scores that correlate different aspects of patient data (comorbidities, vital signs, and others) to risk of thrombosis, such as the POMPE-C, which stratifies risk of mortality due to pulmonary embolism in patients with cancer, who typically have higher rates of thrombosis. [ 37 ]  Also, there are several predictive scores for thromboembolic events, such as Padua, [ 38 ]  Khorana, [ 39 ] [ 40 ]  and  ThroLy score . [ 41 ]


Fibrinolysis  is the physiological breakdown of blood clots by enzymes such as  plasmin .


Organisation: following the thrombotic event, residual vascular thrombus will be re-organised histologically with several possible outcomes. For an occlusive thrombus (defined as thrombosis within a small vessel that leads to complete occlusion),  wound healing  will reorganise the occlusive thrombus into collagenous  scar  tissue, where the scar tissue will either permanently obstruct the vessel, or contract down with  myofibroblastic  activity to unblock the  lumen . For a mural thrombus (defined as a thrombus in a large vessel that restricts the blood flow but does not occlude completely), histological reorganisation of the thrombus does not occur via the classic  wound healing  mechanism. Instead, the  platelet-derived growth factor  degranulated by the clotted  platelets  will attract a layer of  smooth muscle  cells to cover the clot, and this layer of mural smooth muscle will be vascularised by the blood inside the vessel lumen rather than by the  vasa vasorum . [ citation needed ]


Ischemia/infarction: if an arterial thrombus cannot be lysed by the body and it does not embolise, and if the thrombus is large enough to impair or occlude blood flow in the involved artery, then local  ischemia  or  infarction  will result. A  venous thrombus  may or may not be ischemic, since veins distribute deoxygenated blood that is less vital for cellular metabolism. Nevertheless, non-ischemic venous thrombosis may still be problematic, due to the swelling caused by blockage to venous drainage. In  deep vein thrombosis  this manifests as pain, redness, and swelling; in  retinal vein occlusion  this may result in  macular oedema  and  visual acuity  impairment, which if severe enough can lead to blindness.


A thrombus may become detached and enter circulation as an  embolus , finally lodging in and completely obstructing a blood vessel, which unless treated very quickly will lead to tissue necrosis (an  infarction ) in the area past the occlusion. Venous thrombosis can lead to pulmonary embolism when the migrated embolus becomes lodged in the lung. In people with a "shunt" (a connection between the pulmonary and systemic circulation), either in the heart or in the lung, a venous clot can also end up in the arteries and cause arterial embolism. [ citation needed ]


Arterial embolism can lead to obstruction of blood flow through the blood vessel that is obstructed by it, and a lack of oxygen and nutrients ( ischemia ) of the downstream tissue. The tissue can become irreversibly damaged, a process known as  necrosis . This can affect any organ; for instance, arterial embolism of the brain is one of the causes of stroke. [ citation needed ]


The use of  heparin  following surgery is common if there are no issues with bleeding. Generally, a risk-benefit analysis is required, as all anticoagulants lead to an increased risk of bleeding. [ 42 ]  In people admitted to hospital, thrombosis is a major cause for complications and occasionally death. In the UK, for instance, the Parliamentary  Health Select Committee  heard in 2005 that the annual rate of death due to thrombosis was 25,000, with at least 50% of these being hospital-acquired. [ 43 ]  Hence  thromboprophylaxis  (prevention of thrombosis) is increasingly emphasized. In patients admitted for surgery, graded  compression stockings  are widely used, and in severe illness, prolonged immobility and in all  orthopedic surgery ,  professional guidelines  recommend  low molecular weight heparin  (LMWH) administration, mechanical calf compression or (if all else is contraindicated and the patient has recently developed deep vein thrombosis) the insertion of a  vena cava filter . [ 44 ] [ 45 ]  In patients with medical rather than surgical illness, LMWH too is known to prevent thrombosis, [ 45 ] [ 46 ]  and in the United Kingdom the  Chief Medical Officer  has issued guidance to the effect that preventative measures should be used in medical patients, in anticipation of formal guidelines. [ 43 ]


The treatment for thrombosis depends on whether it is in a vein or an artery, the impact on the person, and the risk of complications from treatment. [ citation needed ]


Warfarin  and  vitamin K antagonists  are  anticoagulants  that can be taken orally to reduce thromboembolic occurrence. Where a more effective response is required, heparin can be given (by injection) concomitantly. As a side effect of any anticoagulant, the risk of bleeding is increased, so the  international normalized ratio  of blood is monitored. Self-monitoring and self-management are safe options for competent patients, though their practice varies. In Germany, about 20% of patients were self-managed while only 1% of U.S. patients did home self-testing (according to one 2012 study). [ 47 ]  Other medications such as  direct thrombin inhibitors  and  direct Xa inhibitors  are increasingly being used instead of warfarin. [ citation needed ]


Thrombolysis  is the pharmacological destruction of blood clots by administering  thrombolytic drugs  including  recombinant tissue plasminogen activator , which enhances the normal destruction of blood clots by the body's enzymes. This carries an increased risk of bleeding so is generally only used for specific situations (such as severe stroke or a massive pulmonary embolism). [ 48 ]


Arterial thrombosis may require surgery if it causes  acute limb ischemia . [ citation needed ]


Mechanical clot retrieval and catheter-guided thrombolysis are used in certain situations. [ 49 ]


Arterial thrombosis is platelet-rich, and inhibition of platelet aggregation with  antiplatelet drugs  such as  aspirin  may reduce the risk of recurrence or progression. [ 50 ]


With reperfusion comes ischemia/reperfusion (IR) injury (IRI), which paradoxically causes cell death in reperfused tissue [ 51 ]  and contributes significantly to post-reperfusion mortality and morbidity. [ 52 ] [ 53 ]  For example, in a feline model of intestinal ischemia, four hours of ischemia resulted in less injury than three hours of ischemia followed by one hour of reperfusion. [ 51 ]  In ST-elevation myocardial infarction (STEMI), IRI contributes up to 50% of final infarct size despite timely primary percutaneous coronary intervention. This is a key reason for the continued high mortality and morbidity in these conditions, despite endovascular reperfusion treatments and continuous efforts to improve timeliness and access to these treatments. Hence, protective therapies are required to attenuate IRI alongside reperfusion in acute ischemic conditions to improve clinical outcomes. [ 54 ]  Therapeutic strategies that have potential to improve clinical outcomes in reperfused STEMI patients include  remote ischemic conditioning  (RIC), exenatide, and metoprolol. These have emerged amongst a multitude of cardioprotective interventions investigated with largely neutral clinical data. [ 55 ]  Of these, RIC has the most robust clinical evidence, especially in the context of STEMI, but also emerging for other indications such as acute ischemic stroke and aneurysmal subarachnoid hemorrhage. [ 54 ]


Treatment options for full-term and preterm babies who develop thromboembolism include expectant management (with careful observation), nitroglycerin ointment,  pharmacological therapy  (thrombolytics and/or anticoagulants), and surgery. [ 19 ]  The evidence supporting these treatment approaches is weak. For anticoagulant treatment, it is not clear if unfractionated and/or low molecular weight heparin treatment is effective at decreasing mortality and serious adverse events in this population. [ 19 ]   There is also insufficient evidence to understand the risk of adverse effects associated with these treatment approaches in term or preterm infants. [ 19 ]


Thrombosis prevention  or  thromboprophylaxis  is  medical treatment  to prevent the development of  thrombosis  ( blood clots  inside  blood vessels ) in those considered at risk for developing thrombosis. [ 1 ]  Some people are at a higher  risk  for the formation of blood clots than others, such as those with  cancer  undergoing a surgical procedure. [ 2 ] [ 3 ]  Prevention measures or interventions are usually begun after surgery as the associated immobility will increase a person's risk. [ 4 ]


Blood thinners  are used to prevent clots, these blood thinners have different effectiveness and safety profiles. A 2018 systematic review found 20 studies that included 9771 people with cancer. The evidence did not identify any difference between the effects of different blood thinners on death, developing a clot, or  bleeding . [ 2 ]  A 2021 review found that  low molecular weight heparin  (LMWH) was superior to unfractionated  heparin  in the initial treatment of  venous thromboembolism  for people with cancer. [ 3 ]


There are medication-based  interventions  and non-medication-based interventions. [ 4 ]  The risk of developing blood clots can be lowered by life style modifications, the discontinuation of  oral contraceptives , and  weight loss . In those at high risk both interventions are often used. [ 1 ]  The treatments to prevent the formation of blood clots is balanced against the risk of bleeding. [ 5 ]


One of the goals of blood clot prevention is to limit  venous stasis  as this is a significant risk factor for forming blood clots in the  deep veins  of the legs. [ 6 ]  Venous stasis can occur during the long periods of  not moving . Thrombosis prevention is also recommended during air travel. [ 7 ]  Thrombosis prophylaxis is effective in preventing the formation of blood clots, their lodging in the veins, and their developing into  thromboemboli  that can travel through the  circulatory system  to cause blockage and subsequent  tissue death  in other  organs . [ 1 ]   Clarence Crafoord  is credited with the first use of thrombosis prophylaxis in the 1930s.


The development of blood clots can be interrupted and prevented by the use of medication, changing  risk factors  and other interventions. Some risk factors can be modified. These would be losing weight, increasing exercise and the cessation of oral contraceptives. Moving during periods of travel is a modifiable behavior. Preventing blood clots includes the use of medications that interrupt the complex  clotting cascade  and changing the proteins that are needed for clotting.  Antiplatelet  drugs also have an effect in preventing the formation of clots. [ citation needed ]


Thrombosis prophylaxis is not only used for the prevention of  deep vein thrombosis , but can be initiated for the prevention of the formation of blood clots in other organs and circumstances unrelated to deep vein thrombosis: [ citation needed ]


The risk of developing deep vein thrombosis, or pulmonary embolism is different than the total risk of the formation of blood clots. This is due to the observation that not all blood clots form in the lower legs. Most hospitalized medical patients have at least 1 risk factor for thrombosis that progresses to thromboembolism and this risk persists weeks after discharge. Those who remain undiagnosed and not treated prophylactically have a 26% chance of developing a fatal embolism. Another 26% develop another embolism. Between 5% and 10% of all in hospital deaths are due to pulmonary embolism (as a consequence of thrombosis). Estimates of the incidence of pulmonary embolism in the US is 0.1% persons/year. Hospital admissions in the US for pulmonary embolism are 200,000 to 300,000 yearly. [ 10 ]  Thrombosis that develops into DVT will affect 900,000 people and kill up to 100,000 in the US. On average 28,726 hospitalized adults aged 18 and older with a VTE blood clot diagnosis die each year. [ 11 ]  Risk of thrombosis is related to hospitalization. [ 4 ]  In 2005 the UK the Parliamentary  Health Select Committee  determined the annual rate of death due to thrombosis was 25,000 with at least 50% being hospital-acquired. [ 12 ]


The type of surgery performed prior to the formation of blood clots influences the risk.
Without prophylactic interventions, the calculated incidence of clot formation in the lower leg veins after surgery is:


As the population of the US ages, the development of blood clots is becoming more common. [ 14 ]


Some risk factors for developing blood clots are considered higher that others. One scoring system analyzes the probability for clot formation by assigning a point value system to significant risk factors. [ 15 ]  The benefit of treating those who are at low risk of developing blood clots may not outweigh the higher risks of significant bleeding. [ 16 ]


[ 1 ] [ 20 ] [ 14 ]


Developing blood clots is more probable after the first episode. Risk assessment and intervention for those with one or more episodes of deep vein thrombosis or blood clots in the veins utilizes the Well's test. It has been inconsistently modified by a number of publishers with the results listed below: [ 28 ]


Scoring:


The  Centers for Disease Control and Prevention  have issued general guidelines describing the interventions that can be taken to reduce the risk of the formation of blood clots:


The Centers for Disease Control and Prevention recommend the following:


Seat-edge pressure from the seat on an airplane on the  popliteal area  may contribute to vessel wall damage as well as  venous stasis .  Coagulation  activation may result from an interaction between cabin conditions (such as  hypobaric   hypoxia ) and individual risk factors for the formation of blood clots. Studies of the  pathophysiologic mechanisms  for the increased risk of  Venous thrombosis embolism  or VTE after long-distance travel have not produced consistent results, but venous stasis appears to play a major role; other factors specific to air travel may increase coagulation activation, particularly in passengers with individual risk factors for VTE. [ 30 ]


Mechanical compression devices are used for prevention of thrombosis and are beneficial enough to be used by themselves with patients at low to moderate risk. [ 4 ]  The use of fitted  intermittent pneumatic compression devices  before, during and after procedures is used in inpatient settings. It consists of an air pump and inflatable auxiliary compartments that sequentially inflates and deflated to provide an external 'pump' that returns venous blood toward the heart. [ 31 ]  The use of intermittent pneumatic compression is common. [ 31 ] [ 19 ] [ 5 ]  These devices are also placed on a surgical patient in the operating room (the intra-surgical period) and remain on the person while recovering from the surgery. [ 32 ]


The application of  antiembolism stockings  can be used to prevent thrombosis. [ 4 ]  The correct use and properly fitted graded compression stockings can reduce the rate of thrombosis by 50%. [ 15 ] [ 19 ] : 745–46   Contraindications for the use of antiembolism stockings include the presence of advanced peripheral and obstructive arterial disease, septic phlebitis, heart failure, open wounds, dermatitis and peripheral neuropathy. [ 33 ]  Differences between the use of thigh-high compression stockings and shorter types to prevent blood clots exist, but remain inconsistent. [ 4 ] [ 5 ]


There has been some success in preventing blood clots by an early risk assessment upon admission to the hospital, which is a strategy recognized by the Centers for Disease Control and Prevention. Hospitals that have participated in this effort to reduce the incidence of thrombosis found that rates of DVT decreased in some instances. [ 34 ]  Some hospitals developed a mandatory assessment quantifying the risk for developing blood clots and a plan of care developed from the results. The person's risk for developing blood clots is entered into their record, 'following' them through their treatment regime. If the hospital stay exceeds three days, the person will be reassessed for risk. Clinicians are then able to apply protocols for prevention based upon best clinical practices. [ 35 ] [ 36 ]


Immobility is a significant risk factor in the development of thrombosis. [ 37 ] [ 38 ] [ 22 ] [ 25 ]  Immediate post-surgical interventions, such as out of bed orders (OOB), are typically ordered by the physician to prevent thrombosis. These orders, typically delegated to a nurse, but may include the participation of a physical therapist and others trained to perform the intervention, are to perform range of motion (ROM) activities that include: muscle contractions of the lower legs for those who are very weak, moving the feet, wiggling the toes, bending the knees, raise and lower the legs. In addition, changes in positioning prevents immobility and shifts areas of venous stasis. If the person is too weak to perform these preventative activities, hospital personnel will perform these movements independently. Exercise of the lower extremities is a post-operative method of prophylaxis. Nursing personnel will often perform range of motion exercises and encourage frequent moving of the legs, feet, and ankles. Frequent positioning changes and adequate fluid intake. After a surgical procedure, ambulation as soon as possible is prophylactic in preventing the formation of blood clots. [ 38 ] [ 22 ] [ 25 ]


Early ambulation also prevents venous stasis and physicians order OOB activities on the same day of surgery. This is accomplished in increments. The progression of increasing mobility proceeds by: raising the head of the bed, sitting up in bed, moving to the edge of the bed, dangling the legs off the bed and then ambulating to a close chair. [ 19 ] [ 25 ]


Patient education and compliance reduces the risk of developing blood clots. These exercises and use of equipment and follow up by clinicians reduces the risk of developing blood clots. [ 25 ]


Note that if a blood clot has already formed in the deep veins of the leg, bedrest is usually prescribed and the treatment to prevent bloods with physical intervention is  contraindicated . [ citation needed ]


Thromboprophylaxis, such as  anticoagulants  or perioperative heparin, is effective for hospitalized patients at risk for VTE. [ 2 ] [ 39 ]  Additional risk factors such as obesity, disease, malignancies, long surgeries, and immobility may influence the prescribed dosage. Anticoagulant medications may prevent the formation of blood clots in people who are at high risk for their development. [ 4 ]  Treating blood clots that have already formed is managed by the use of anti-hemolytic ("clot busters"). Despite its effectiveness, the use of thromboprophylaxis remains under-utilized, though alerts (computer or human) in hospitals are associated with increased prescription and reductions in symptomatic VTE. [ 39 ]  The list below describes some of the more common medications used to prevent blood clots. [ 24 ]  Note that generally since blood clotting is inhibited, a side effect typically is increased bleeding, though it can be reversed by administering a medication that stops the bleeding or by discontinuation of the medication itself. Anti-coagulant administration is often given before the start of the operation. [ 25 ]  Medications that inhibit blood clot formation include:


Adding heparin to the use of compression stockings may prevent thrombosis for those of higher risk. [ 4 ] [ 47 ]


The discontinuation of contraceptives also prevents blood clots. [ 15 ]


The therapeutic effects of warfarin may be decreased by  valerian . Anticoagulants can be affected by  chamomile .  Dong quai , garlic,  ginger ,  Ginkgo biloba ,  bilberry   and  feverfew  can increase bleeding time. These same  herbal supplements  taken with warfarin increased  prothrombin time . [ 24 ]


By containing significant content of  vitamin K , some foods act as  antagonists  to antiplatelet and anticoagulant medications; these include green leafy vegetables, like  spinach ,  legumes , and  broccoli . [ 24 ]


Preventing blood clots with medication is not considered safe in the following circumstances:


An international registry and risk assessment calculator is being used to centralize data on post-surgical venous thrombosis and its prevention. [ 53 ]  Hospitals are implementing a  multi-disciplinary approach  to prevent of blood clots. This includes adequate assessment of the risks, follow up on missed doses of medication and instituting a 'patient-centered' approach endorsed by the  Joint Commission . [ 34 ]  Recommendations regarding the prevention of blood clots vary widely between clinicians and treatment facilities. Research continues to clarify these discrepancies. [ 5 ]  The metabolic state of hypercoagulability (the tendency to form blood clots) tests are being developed. These include the evaluation of the  thrombin–antithrombin complexes  (TAT), low levels of the anticoagulants ATIII and protein C, but these tests are not yet widely available. [ 13 ]


Using Wikipedia for Research


A  thrombus  ( pl.   thrombi ), colloquially called a  blood clot , is the final product of the  blood coagulation  step in  hemostasis . There are two components to a thrombus: aggregated  platelets  and  red blood cells  that form a plug, and a mesh of cross-linked  fibrin  protein. The substance making up a thrombus is sometimes called  cruor . A thrombus is a healthy response to  injury  intended to stop and prevent further bleeding, but can be harmful in  thrombosis , when a clot obstructs blood flow through a healthy  blood vessel  in the  circulatory system .


In the  microcirculation  consisting of the very small and smallest blood vessels the  capillaries , tiny thrombi known as microclots can obstruct the flow of blood in the capillaries. This can cause a number of problems particularly affecting the  alveoli  in the  lungs  of the  respiratory system  resulting from reduced oxygen supply. Microclots have been found to be a characteristic feature in severe cases of  COVID-19  and in  long COVID . [ 1 ]


Mural thrombi are thrombi that adhere to the wall of a large  blood vessel  or  heart chamber . [ 2 ]  They are most commonly found in the  aorta , the largest  artery  in the body, more often in the  descending aorta , and less often in the  aortic arch  or  abdominal aorta . [ 2 ]  They can restrict blood flow but usually do not block it entirely. They appear grey-red along with alternating light and dark lines (known as  lines of Zahn ) which represent bands of white blood cells and red blood cells (darker) entrapped in layers of fibrin. [ 3 ]


Thrombi are classified into two major groups depending on their location and the relative amount of platelets and red blood cells. [ 4 ]  The two major groups are:


In the  microcirculation  consisting of the very small and smallest blood vessels, the  capillaries , tiny thrombi (microthrombi) [ 5 ]  known as microclots can obstruct the flow of blood in the capillaries. Microclots are small clumps of blood that form within the circulation, usually as a result of a larger thrombus breaking down into smaller pieces. They can be a cause for concern as they can lead to blockages in small vessels and restrict blood flow, leading to tissue damage and potentially causing  ischemic events . [ citation needed ]


Microclots can cause a number of problems particularly affecting the  alveoli  in the  lungs  of the  respiratory system , resulting from reduced oxygen supply. Microclots have been found to be a characteristic feature in severe cases of  COVID-19 , and in  long COVID . [ 1 ] [ 6 ]


Mural thrombi form and adhere on the inner wall of a large  blood vessel  or  heart chamber , often as a result of blood stasis. [ 2 ]  They are most commonly found in the  aorta , the largest  artery  in the body, more often in the  descending aorta , and less often in the  aortic arch  or  abdominal aorta . [ 2 ]  They can restrict blood flow but usually do not block it entirely. Mural thrombi are usually found in vessels already damaged by  atherosclerosis . [ 3 ]


A mural thrombus can affect any heart chamber. When found in the  left ventricle  it is often a result of a heart attack complication. The thrombus in this case can separate from the chamber, be carried through arteries and block a blood vessel. [ 2 ]  They appear grey-red with alternating light and dark lines (known as  lines of Zahn ) which represent bands of white blood cells and red blood cells (darker) entrapped in layers of  fibrin . [ citation needed ]


It was suggested over 150 years ago that thrombus formation is a result of abnormalities in blood flow, vessel wall, and blood components. This concept is now known as  Virchow's triad . The three factors have been further refined to include circulatory stasis, vascular wall injury, and hypercoagulable state, all of which contribute to increased risk for venous thromboembolism and other cardiovascular diseases. [ 4 ]


Virchow's triad  describes the  pathogenesis  of thrombus formation: [ 7 ] [ 8 ]


Disseminated intravascular coagulation  (DIC) involves widespread microthrombi formation throughout the majority of the blood vessels. This is due to excessive consumption of coagulation factors and subsequent activation of  fibrinolysis  using all of the body's available  platelets  and clotting factors. The result is hemorrhaging and ischemic necrosis of tissue/organs. Causes are  septicaemia , acute  leukaemia ,  shock , snake bites,  fat emboli  from broken bones, or other severe traumas. DIC may also be seen in  pregnant females . Treatment involves the use of  fresh frozen plasma  to restore the level of clotting factors in the blood, as well as platelets and heparin to prevent further thrombi formation. [ citation needed ]


A thrombus occurs when the hemostatic process, which normally occurs in response to injury, becomes activated in an uninjured or slightly injured vessel. A thrombus in a large blood vessel will decrease blood flow through that vessel (termed a mural thrombus). In a small blood vessel, blood flow may be completely cut off (termed an occlusive thrombus), resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is considered an  embolus . [ citation needed ]  If an embolus becomes trapped within a blood vessel, it blocks blood flow and is termed as an embolism. Embolisms, depending on their specific location, can cause more significant effects like strokes, heart attacks, or even death. [ 11 ]


Some of the conditions which increase the risk of blood clots developing include  atrial fibrillation  (a form of  cardiac arrhythmia ), heart valve replacement, a recent  heart attack  (also known as a  myocardial infarction ), extended periods of inactivity (see  deep venous thrombosis ), and genetic or disease-related deficiencies in the blood's clotting abilities. [ citation needed ]


Platelet activation occurs through injuries that damage the  endothelium  of the blood vessels, exposing the enzyme called  factor VII , a protein normally circulating within the vessels, to the  tissue factor , which is a protein encoded by the F3 gene.
The platelet activation can potentially cause a cascade, eventually leading to the formation of the thrombus. [ 12 ]  This process is regulated through  thromboregulation .


Anticoagulants  are drugs used to prevent the formation of blood clots, reducing the risk of  stroke ,  heart attack  and  pulmonary embolism .  Heparin  and  warfarin  are used to inhibit the formation and growth of existing thrombi, with the former used for acute anticoagulation while the latter is used for long-term anticoagulation. [ 8 ]  The mechanism of action of heparin and warfarin are different as they work on different pathways of the  coagulation cascade . [ 13 ]


Heparin works by binding to and activating the enzyme inhibitor  antithrombin III , an enzyme that acts by inactivating thrombin and factor Xa. [ 13 ]  In contrast, warfarin works by inhibiting  vitamin K epoxide reductase , an enzyme needed to synthesize vitamin K dependent clotting factors II, VII, IX, and X. [ 13 ] [ 14 ]  Bleeding time with heparin and warfarin therapy can be measured with the partial thromboplastin time (PTT) and  prothrombin time  (PT), respectively. [ 14 ]


Once clots have formed, other drugs can be used to promote  thrombolysis  or clot breakdown.  Streptokinase , an enzyme produced by  streptococcal bacteria , is one of the oldest thrombolytic drugs. [ 14 ]  This drug can be administered  intravenously  to dissolve blood clots in  coronary vessels . However, streptokinase causes systemic fibrinolytic state and can lead to bleeding problems.  Tissue plasminogen activator  (tPA) is a different enzyme that promotes the degradation of fibrin in clots but not free fibrinogen. [ 14 ]  This drug is made by transgenic bacteria and converts plasminogen into the clot-dissolving enzyme,  plasmin . [ 15 ]  Recent research indicates that tPA could have toxic effects in the central nervous system. In cases of severe stroke, tPA can cross the  blood–brain barrier  and enter interstitial fluid, where it then increases excitotoxicity, potentially affecting permeability of the blood–brain barrier, [ 16 ]  and causing cerebral hemorrhage. [ 17 ]


There are also some anticoagulants that come from animals that work by dissolving  fibrin . For example,  Haementeria ghilianii , an  Amazon   leech , produces an enzyme called  hementin  from its  salivary glands . [ 18 ]


Thrombus formation can have one of four outcomes: propagation, embolization, dissolution, and organization and recanalization. [ 19 ]


Toxic granulation  refers to dark coarse granules found in  granulocytes , particularly  neutrophils , in patients with inflammatory conditions. [ 1 ]


Along with  Döhle bodies  and  toxic vacuolation , which are two other findings in the  cytoplasm  of granulocytes, toxic granulation is a  peripheral blood film  finding suggestive of an  inflammatory process . [ 1 ]  Toxic granulation is often found in patients with  bacterial infection  and  sepsis , [ 1 ] [ 2 ]  although the finding is nonspecific. [ 3 ]  Patients being treated with  chemotherapy [ 3 ]  or  granulocyte colony stimulating factor , a  cytokine  drug, may also exhibit toxic granulation. [ 2 ]


Toxic granules are mainly composed of  peroxidase  and  acid hydrolase  enzymes, [ 3 ]  and are similar in composition to the primary granules found in immature granulocytic cells like  promyelocytes . [ 4 ] [ 5 ]  Although normal, mature neutrophils do contain some primary granules, the granules are difficult to identify by light microscopy because they lose their dark blue colour as the cells mature. Toxic granulation thus represents abnormal maturation of neutrophils. [ 6 ]


Patients with the inherited condition  Alder-Reilly anomaly  exhibit very large, darkly staining granules in their neutrophils, which can be confused with toxic granulation. [ 2 ] [ 7 ]


Toxic vacuolation , also known as  toxic vacuolization , [ 1 ]  is the formation of  vacuoles  in the  cytoplasm  of  neutrophils  in response to severe  infections  or  inflammatory conditions . [ 2 ] [ 3 ]


Toxic vacuolation is associated with  sepsis , particularly when accompanied by  toxic granulation . [ 4 ]  The finding is also associated with bacterial infection, [ 3 ]  alcohol toxicity, liver failure, [ 4 ]  and treatment with  granulocyte colony-stimulating factor , a  cytokine  drug used to increase the  absolute neutrophil count  in patients with  neutropenia . [ 5 ] [ 6 ]


The formation of toxic vacuoles represents increased  phagocytic  activity, which is stimulated by the release of  cytokines  in response to inflammation or tissue injury. Toxic vacuolation frequently occurs in conjunction with  toxic granulation  and  Döhle bodies  in inflammatory states, and these findings are collectively referred to as  toxic changes . [ 5 ]   Neutrophilia  and  left shift  (the presence of immature neutrophil precursors such as  band neutrophils  and  metamyelocytes  in the peripheral blood) often accompany toxic changes, as these phenomena also occur in response to inflammation. [ 1 ] [ 5 ]


It has been suggested that neutrophil vacuoles not be labelled "toxic vacuoles" unless they are accompanied by other toxic changes, as vacuolation can occur in other conditions. [ 7 ]


Vacuoles may form in neutrophils if a blood sample is left standing for several hours prior to  blood smear  preparation, but this is an artifactual change with no clinical significance. [ 4 ]  Artifactual vacuoles are small and of uniform size and distribution, in contrast to toxic vacuoles whose size and placement are variable. [ 1 ]  Individuals with  neutral lipid storage disease  may exhibit persistent lipid-filled vacuoles in neutrophils and other granulocytes, which is a distinct phenomenon termed  Jordans' anomaly . [ 8 ]


Red blood cells ( erythrocytes ) from donors contain normal  hemoglobin  (HbA), and transfusion of normal red blood cells into people with  sickle cell disease  reduces the percentage of red cells in the circulation containing the abnormal hemoglobin (HbS). [ 1 ]  Although transfusion of donor red blood cells can ameliorate and even prevent complications of sickle cell disease in certain circumstances, transfusion therapy is not universally beneficial in sickle cell disease. [ 2 ]


There are two main types of transfusion, simple red cell transfusion and exchange transfusion.


Involves transfusing red blood cells without removing any of the patient’s blood. [ 3 ]  It is used when the patient's hemoglobin is much lower than normal, for example an  aplastic crisis . [ 4 ]


Exchange transfusion involves removal of the patient’s blood and replacement with donor red blood cells. [ 3 ]  It is used to treat life-threatening complications of sickle cell disease such as  stroke  or acute chest crisis. [ 4 ]


There are three main benefits of an exchange transfusion compared to a simple transfusion, these relate primarily to the ability to remove  hemoglobin S  containing red blood cells: [ 5 ]


However, there are also potential risks associated with an exchange transfusion:


The exchange is performed using a machine ( pheresis ). This method rapidly and substantially reduces the concentration of sickle cells within the blood without increasing the overall  hematocrit  or  blood viscosity . [ citation needed ]


The exchange is performed manually. It refers to manually phlebotomizing a percentage of the patient’s blood prior to or concomitantly with giving a red cell transfusion. [ citation needed ]


Red cell transfusions can be further classified as episodic or chronic. [ 3 ]


Episodic transfusion is used either acutely in response to a complication of sickle cell disease such as acute chest syndrome or to prevent complications prior to surgery. [ 3 ]


Chronic transfusion is used when sustained, low levels of HbS are needed to prevent sickle cell-related complications, most commonly stroke in children. [ 3 ]


Transfusion therapy for sickle-cell disease entails the use of red blood cell transfusions in the management of acute cases of sickle cell disease and as a prophylaxis to prevent complications by decreasing the number of red blood cells (RBC) that can sickle by adding normal red blood cells. [ citation needed ]


In children prophylactic chronic red blood cell (RBC) transfusion therapy has been shown to be efficacious to a certain extent in reducing the risk of first stroke or  silent stroke  when  transcranial Doppler  (TCD)  ultrasonography  shows abnormal increased cerebral blood flow velocities. In those who have sustained a prior stoke event it also reduces the risk of recurrent stroke and additional silent strokes. [ 6 ] [ 7 ] [ 8 ]  There is no evidence for the use of red blood cell transfusion in adults to prevent primary stroke, although it is recommended to prevent secondary stroke. [ 8 ] [ 9 ] [ 10 ] [ 11 ]


In children and adults red blood cell transfusion to increase the hemoglobin level to 100 g/L has been shown to decrease the risk of sickle cell-related complications. [ 2 ]  However, this has not been seen in all studies, and has only been demonstrated for African  haplotypes  of Hemoglobin SS. [ 12 ] [ 13 ]


In children who have been given transfusions to prevent stroke there was also a reduction in the number of children who developed acute chest crises. [ 13 ]  There is no evidence about whether or not red cell transfusions prevent chronic lung complications. [ 14 ]


This should be suspected if there is a significant drop in the hemoglobin level compared to the patient's usual hemoglobin level which is associated with a low level of  reticulocytes . This is usually due to infection with  erythrovirus B19  (previously known as parvovirus B19). [ 11 ]  The  anemia  is usually severe with an average drop in hemoglobin of 40 g/L, and is usually treated with a simple transfusion. [ 11 ]


Acute splenic and hepatic sequestration associated with severe anemia requires a simple transfusion to raise the hemoglobin. [ 3 ] [ 11 ]


Red cell transfusions are used to treat patients with acute chest crisis and  respiratory compromise . [ 9 ] [ 2 ]  Exchange transfusion is recommended for those patients who have a higher hemoglobin (> 90g/L), those who have not improved after a simple transfusion, or those who have severe respiratory compromise. [ 11 ]


Red cell alloimmunisation is common in people with sickle cell disease who receive transfusions in Europe and North America. [ 4 ]  This is because there are ethnic differences in the frequencies of  blood group antigens . [ 4 ]  Blood donors are usually  Caucasian  whereas the blood transfusion recipients usually have an African or Afro-Caribbean ancestry. [ 4 ] [ 15 ]  Extended phenotype matching of red blood cells (matching  Rh  and  Kell  blood groups as well as  ABO ) decreases the risk of alloimmunisation, but it still occurs. [ 4 ]


Each unit of transfused blood has approximately 250 mg of iron, with each successive transfusion, patients receiving chronic transfusion therapy accumulate iron in various tissues in the body as the body has no way to excrete the excess, this is a cause of increased morbidity and mortality. [ 16 ]  The effects of iron overload are countered by  chelation therapy [ 17 ]  Guidelines recommend if patients are receiving regular or intermittent transfusions they should be monitored for iron overload. [ 4 ]


In  hemocytometry ,  Türk's solution  (or  Türk's fluid ) is a  hematological stain  (either  crystal violet  or aqueous  methylene blue ) prepared in 99%  acetic acid  (glacial) [ 1 ]  and  distilled water . The solution destroys the
 red blood cells  and platelets within a blood sample (acetic acid being the main  lyzing agent ), and stains the nuclei of the  white blood cells , making them easier to see and count. [ 1 ]


Türk's solution is intended for use in determining total leukocyte count in a defined volume of blood. Erythrocytes are hemolyzed while leukocytes are stained for easy visualization. [ 1 ] [ 2 ]


Composition of Türk's solution is as follows:


Vascular occlusion  is a blockage of a blood vessel, usually with a  clot .  It differs from  thrombosis  in that it can be used to describe any form of blockage, not just one formed by a clot.  When it occurs in a major  vein , it can, in some cases, cause  deep vein thrombosis .  The condition is also relatively common in the  retina , and can cause partial or total loss of vision.  An occlusion can often be diagnosed using  Doppler sonography  (a form of  ultrasound ). [ 1 ] [ 2 ]


Some medical procedures, such as  embolisation , involve occluding a blood vessel to treat a particular condition.  This can be to reduce pressure on  aneurysms  (weakened blood vessels) or to restrict a  haemorrhage .  It can also be used to reduce blood supply to tumours or growths in the body, and therefore restrict their development.  Occlusion can be carried out using a  ligature ; by implanting small coils which stimulate the formation of clots; or, particularly in the case of  cerebral aneurysms , by  clipping . [ 3 ] [ 4 ]


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


In medicine,  venipuncture  or  venepuncture  is the process of obtaining intravenous access for the purpose of venous  blood sampling  (also called  phlebotomy ) or  intravenous therapy . In healthcare, this procedure is performed by  medical laboratory scientists ,  medical practitioners , some  EMTs ,  paramedics ,  phlebotomists ,  dialysis  technicians, and other nursing staff. [ 1 ]  In  veterinary medicine , the procedure is performed by  veterinarians  and  veterinary technicians .


It is essential to follow a standard procedure for the collection of blood specimens to get accurate laboratory results. Any error in collecting the blood or filling the test tubes may lead to erroneous laboratory results. [ 2 ]


Venipuncture is one of the most routinely performed invasive procedures and is carried out for any of five reasons:


Blood analysis  is an important diagnostic tool available to clinicians within healthcare.


Blood is most commonly obtained from the superficial veins of the upper limb. [ 1 ]  The  median cubital vein , which lies within the  cubital fossa  anterior to the elbow, is close to the surface of the skin without many large nerves positioned nearby. Other veins that can be used in the cubital fossa for venipuncture include the  cephalic ,  basilic , and  median antebrachial veins . [ 4 ]


Minute quantities of blood may be taken by  fingerstick sampling  and collected from infants by means of a  heelprick  or from scalp veins with a  winged infusion needle .


Phlebotomy (incision into a vein) is also the treatment of certain diseases such as  hemochromatosis  and primary and secondary  polycythemia .


A 1996 study of blood donors (a larger needle is used in blood donation than in routine venipuncture) found that 1 in 6,300 donors sustained a nerve injury. [ 5 ]


Risk and side affects can include a variety of things. Dizziness, sweating, and a drop in your heart rate and blood pressure.  [1] [ 6 ]


There are many ways in which blood can be drawn from a vein, and the method used depends on the person's age, the equipment available, and the type of tests required.


Most  blood collection  in the US, UK, Canada and Hong Kong is done with an evacuated tube system. Two common systems are  Vacutainer  (Becton, Dickinson and company) and Vacuette (Greiner Bio-One). The equipment consists of a plastic adapter, also known as a tube or needle holder/hub, a hypodermic needle and a vacuum tube. Under certain circumstances, a syringe may be used, often with a  butterfly needle , which is a plastic catheter attached to a short needle. In the developing world, the evacuated tube system is the preferred method of drawing blood. [ citation needed ]


Greiner Bio-One manufactured the first ever plastic evacuated blood collection tube in 1985 under the VACUETTE brand name. Today, many companies sell vacuum tubes as the patent for this device is now in the public domain. These tubes are manufactured with a specific volume of gas removed from the sealed tube. When a needle from a hub or transfer device is inserted into the stopper, the tube's vacuum automatically pulls in the required volume of blood. [ citation needed ]


The basic Evacuated Tube System (ETS) consists of a needle, a tube holder, and the evacuated tubes. The needle is attached to the tube holder by the phlebotomist prior to collection, or may come from the manufacturer as one unit. The needle protrudes through the end of the tube holder, and has a needle on each end. After first cleaning the venipuncture site and applying a tourniquet, the phlebotomist uncaps the needle attached to the tube holder, inserts the needle into the vein, then slides evacuated tubes into the tube holder, where the tube's stopper is pierced by the back end of the needle. The vacuum in the tube then automatically draws the needed blood directly from the vein. Multiple vacuum tubes can be attached to and removed in turn from a single needle, allowing multiple samples to be obtained from a single procedure. This is possible due to the multiple sample sleeve, which is a flexible rubber fitting over the posterior end of the needle  cannula  which seals the needle until it is pushed out of the way. This keeps blood from freely draining out of the back of the needle inserted in the vein, as each test tube is removed and the next impaled.  OSHA  safety regulations require that needles or tube holders come equipped with a safety device to cover the needle after the procedure to prevent accidental needle stick injury. [ 7 ]


Fittings and adapters used to fill evacuated tubes from butterfly needle kits and syringes are also available. [ citation needed ]


There are several needle gauges for a phlebotomist to choose from. The most commonly used are as follows: a 21g (green top) needle, a 22g (black top) needle, a 21g (green label) butterfly needle, a 23g (light blue label) butterfly needle, and a 25g (orange or dark blue label) butterfly needle (however this needle is only used in pediatrics or extreme cases as it is so small that it can often result in hemolyzing the blood sample). There are also a variety of tube and bottle sizes and volumes for different test requirements. [ 8 ]


The test tubes in which blood is collected may contain one or more of several additives. In general, tests requiring whole blood call for blood samples collected in test tubes containing some form of the anticoagulant  EDTA . EDTA  chelates  calcium to prevent clotting. EDTA is preferred for hematology tests because it does minimum damage to cell morphology. Sodium citrate is the anticoagulant used in specimens collected for coagulation tests. The majority of chemistry and immunology tests are performed on serum, which is produced by clotting and then separating the blood specimen via centrifuge. These specimens are collected in either a non-additive tube or one containing a  clotting  activator. This clotting activator can interfere with some  assays , and so a plain tube is recommended in these cases, but will delay testing. Tubes containing lithium heparin or sodium heparin are also commonly used for a variety of chemistry tests, as they do not require clotting and can be centrifuged immediately after collection. A combination of  sodium fluoride  and potassium oxalate is used for glucose tests, as these additives both prevent clotting and stop glycolosis, so that blood glucose levels are preserved after collection. [ 9 ]  Another specialty tube is an opaque amber colored tube used to collect blood for light sensitive analytes, such as  bilirubin . [ citation needed ]


Test tubes are labeled with the additive they contain, but the stopper on each tube is color coded according to additive as well. While colors vary between manufacturers, stopper colors generally are associated with each additive as listed below. Because the additives from each tube can be left on the needle used to fill the tubes, they must be drawn in a specific order to ensure that cross contamination will not negatively affect testing of the samples if multiple tubes are to be drawn at once. The "order of draw" varies by collection method. Below in the order of draw generally required for the Evacuated Tube System (ETS) collection method are the most common tubes, listing additive and color: [ 10 ] [ 11 ]


("light blue")


(weak calcium chelator/ anticoagulant )


Plasma separator gel


("navy")


Fluoride Oxalate


Grey, Green, Yellow, Purple


1. Grey (nil) tube
2. Green (TB1 antigen) tube
3. Yellow (TB2 antigen) tube
4. Purple (mitogen) tube


Use of lidocaine  iontophoresis  is effective for reducing pain and alleviating distress during venipuncture in children. [ 19 ]  A needle-free powder  lignocaine  delivery system has been shown to decrease the pain of venipuncture in children. [ 20 ] [ 21 ]  Rapid dermal anesthesia can be achieved by local anesthetic infiltration, but it may evoke anxiety in children frightened by needles or distort the skin, making vascular access more difficult and increasing the risk of needle exposure to health care workers. Dermal anesthesia can also be achieved without needles by the topical application of local anesthetics or by lidocaine iontophoresis. By contrast, noninvasive dermal anesthesia can be established in 5–15 min without distorting underlying tissues by lidocaine iontophoresis, where a direct electric current facilitates dermal penetration of positively charged lidocaine molecules when placed under the positive electrode. [ citation needed ]


One study concluded that the iontophoretic administration of  lidocaine  was safe and effective in providing dermal anesthesia for venipuncture in children 6–17 years old. This technique may not be applicable to all children. Future studies may provide information on the minimum effective iontophoretic dose for dermal anesthesia in children and the comparison of the anesthetic efficacy and satisfaction of lidocaine iontophoresis with topical anesthetic creams and subcutaneous infiltration. [ 19 ]


Non-pharmacological treatments for pain associated with venipuncture in children includes  hypnosis  and distraction. These treatments reduced self reported pain and when combined with  cognitive-behavioural therapy  (CBT) the reduction of pain was even greater.  Other interventions have not been found to be effective and these are suggestion, blowing out air, and distraction with parent coaching did not differ from control for pain and distress. [ 22 ]


Some health care workers prefer to use a  syringe -needle technique for venipuncture.  Sarstedt  manufactures a blood-drawing system (S-Monovette) that uses this principle. [ 23 ]  This method can be preferred on the elderly, those with cancer, severe burns, obesity, or where the veins are unreliable or fragile. Because syringes are manually operated, the amount of suction applied may be easily controlled. This is particularly helpful when veins are small which may collapse under the suction of an evacuated tube. In children or other circumstances where the quantity of blood gained may be limited it can be helpful to know how much blood can be obtained before distributing it amongst the various additives that the laboratory will require. Another alternative is drawing blood from indwelling cannulae. [ 24 ]


There are times when a blood culture collection is required. The culture will determine if there are pathogens in the blood. Normally blood is sterile. When drawing blood from cultures use a sterile solution such as  Betadine  rather than  alcohol . This is done using sterile gloves, while not wiping away the surgical solution, touching the puncture site, or in any way compromising the sterile process. It is vital that the procedure is performed in as sterile a manner as possible as the persistent presence of skin  commensals  in blood cultures could indicate  endocarditis  but they are most often found as contaminants.
It is encouraged to use an abrasive method of skin preparation. This removes the upper layers of dead skin cells along with their contaminating bacteria. [ 25 ]  Povidone-iodine has traditionally been used but in the UK a 2%  chlorhexidine  in 70% ethanol or isopropyl alcohol solution is preferred and time must be allowed for it to dry. The tops of any containers used when drawing a blood culture should also be disinfected using a similar solution. Some labs will actively discourage iodine use where iodine is thought to degrade the rubber stopper through which blood enters the bottle, thus allowing contaminates to enter the container. [ citation needed ]


The blood is collected into special transport bottles, which are like vacuum tubes but shaped differently. The blood culture bottle contains transport media to preserve any microorganisms present while they are being transported to the laboratory for cultures. Because it is unknown whether the pathogens are  anaerobic  (living without oxygen) or  aerobic  (living with oxygen), blood is collected to test for both. The aerobic bottle is filled first, and then the anaerobic bottle is filled. However, if the collection is performed using a syringe, the anaerobic bottle is filled first. If a butterfly collection kit is used, the aerobic bottle is filled first, so that any air in the tubing is released into the oxygen-containing bottle. [ citation needed ]


Specially designed blood culture collection bottles eliminate the need for either the syringe or butterfly collection method. These specially designed bottles have long necks that fit into the evacuated tubes holders that are use for regular venipuncture collection. These bottles also allow for collection of other blood specimens via evacuated tubes, to be collected without additional venipuncture. [ citation needed ]


The amount of blood that is collected is critical for the optimal recovery of microorganisms. Up to 10mL of blood is typical, but can vary according to the recommends of the manufacturer of the collection bottle. Collection from infants and children are 1 to 5 mL. If too little blood is collected, the ratio of blood-to-nutrient broth will inhibit the growth of microorganisms. If too much blood is collected, there is the risk of a hospital-induced anemia and the ratio of blood-to-nutrient broth will tilt in the opposite direction, which also is not conductive to optimal growth. [ citation needed ]


The bottles are then incubated in specialized units for 24 hours before a lab technician studies and/or tests it. This step allows the very small numbers of bacteria (potentially 1 or 2 organisms) to multiply to a level which is sufficient for identification +/-antibiotic resistance testing. Modern blood culture bottles have an indicator in the base which changes color in the presence of bacterial growth and can be read automatically by machine. (For this reason the barcoded stickers found on these bottles should not be removed as they are used by the laboratory's automated systems.) [ citation needed ]


Blood samples from living laboratory animals may be collected using following methods: [ 26 ] [ 27 ]


The volume of the blood sample collection is very important in experimental animals. All nonterminal blood collection without replacement of fluids is limited up to 10% of total circulating blood volume in healthy, normal, adult animals on a single occasion and collection may be repeated after three to four weeks. In case repeated blood samples are required at short intervals, a maximum of 0.6 ml/kg/day or 1.0% of an animal's total blood volume can be removed every 24 hours. The estimated blood volume in adult animals is 55 to 70 ml/kg body weight. Care should be taken for older and obese animals. If blood collection volume exceeds more than 10% of total blood volume, fluid replacement may be required. Lactated Ringer's solution (LRS) is recommended as the best fluid replacement by National Institutes of Health (NIH). If the volume of blood collection exceeds more than 30% of the total circulatory blood volume, adequate care should be taken so that the animal does not develop hypovolemia. [ 27 ]


It is generally not advisable to use  isopropyl alcohol  to cleanse the venipuncture site when obtaining a specimen for a  blood alcohol  test. This has been related largely to the potential legal implications associated with the use of alcohol-based cleaners that could theoretically impact analysis. Numerous police alcohol collection kits have been marketed that incorporate a sodium fluoride/potassium oxalate preservative and non-alcohol-based cleansing agents to ensure proper collection. Using soap and hot water or a  povidone-iodine  swab are advisable alternatives to isopropyl alcohol in this case. [ citation needed ]


Venous thrombosis  is the blockage of a  vein  caused by a  thrombus  (blood clot). A common form of venous thrombosis is  deep vein thrombosis  (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes ) and flows to the lungs to lodge there, it becomes a  pulmonary embolism  (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term  venous thromboembolism  (VTE). [ 2 ]


The initial treatment for VTE is typically either  low-molecular-weight heparin  (LMWH) or  unfractionated heparin , or increasingly with  direct acting oral anticoagulants  (DOAC). Those initially treated with heparins can be switched to other  anticoagulants  ( warfarin , DOACs), although pregnant women and some people with cancer receive ongoing heparin treatment.  Superficial venous thrombosis  or phlebitis affects the superficial veins of the upper or lower extremity and only require anticoagulation in specific situations, and may be treated with anti-inflammatory pain relief only.


There are other less common forms of venous thrombosis, some of which can also lead to pulmonary embolism. Venous  thromboembolism  and superficial vein thrombosis account for about 90% of venous thrombosis. Other rarer forms include  retinal vein thrombosis , mesenteric vein thrombosis (affecting veins draining blood from the gastrointestinal organs),  cerebral venous sinus thrombosis ,  renal vein thrombosis , and ovarian vein thrombosis. [ 3 ]


Superficial venous thromboses  cause discomfort but generally not serious consequences, as do the  deep vein thromboses  (DVTs) that form in the deep veins of the legs or in the pelvic veins. Nevertheless, they can progress to the deep veins through the  perforator veins   or, they can be responsible for a lung embolism mainly if the head of the clot is poorly attached to the vein wall and is situated near the  sapheno-femoral junction . [ citation needed ]


When a blood clot breaks loose and travels in the blood, this is called a  thromboembolism . The abbreviation DVT/PE refers to a VTE where a deep vein thrombosis (DVT) has moved to the lungs (PE or pulmonary embolism). [ 4 ]


Since the veins return  blood  to the  heart , if a piece of a blood clot formed in a vein breaks off it can be transported to the right side of the heart, and from there into the  lungs . A piece of thrombus that is transported in this way is an  embolus : the process of forming a thrombus that becomes embolic is called a  thromboembolism . An embolism that lodges in the lungs is a  pulmonary embolism  (PE). A pulmonary embolism is a very serious condition that can be fatal depending on the dimensions of the embolus. [ citation needed ]


While venous thrombosis of the legs is the most common form, venous thrombosis may occur in other veins. These may have particular specific risk factors: [ 5 ]


Systemic embolism of venous origin can occur in patients with an  atrial  or  ventricular septal defect , or an arteriovenous connection in the lung, through which an embolus may pass into the arterial system. Such an event is termed a  paradoxical embolism . When this affects the blood vessels of the brain it can cause  stroke . [ 6 ]


Venous thrombi are caused mainly by a combination of  venous stasis  and  hypercoagulability —but to a lesser extent endothelial damage and  activation . [ 7 ]  The three factors of stasis, hypercoagulability, and alterations in the blood vessel wall represent  Virchow's triad , and changes to the vessel wall are the least understood. [ 8 ]  Various risk factors increase the likelihood of any one individual developing a thrombosis:


The overall absolute risk of venous thrombosis per 100,000 woman years in current use of  combined oral contraceptives  is approximately 60, compared to 30 in non-users. [ 23 ]  The risk of thromboembolism varies with different types of birth control pills; Compared with combined oral contraceptives containing levonorgestrel (LNG), and with the same dose of estrogen and duration of use, the rate ratio of deep vein thrombosis for combined oral contraceptives with  norethisterone  is 0.98, with  norgestimate  1.19, with  desogestrel  (DSG) 1.82, with  gestodene  1.86, with  drospirenone  (DRSP) 1.64, and with  cyproterone acetate  1.88. [ 23 ]  Venous thromboembolism occurs in 100–200 per 100,000 pregnant women every year. [ 23 ]


Regarding family history, age has substantial  effect modification . For people with two or more affected siblings, the highest incidence rate is found among those ≥70 years of age (390 per 100,000 in men and 370 per 100,000 in women), whereas the highest incidence ratios compared to those without affected siblings occurred at much younger ages (ratio of 4.3 among men 20 to 29 years of age and 5.5 among women 10 to 19 years of age). [ 24 ]


In contrast to the understanding for how arterial thromboses occur, as with  heart attacks , venous thrombosis formation is not well understood. [ 26 ]  With arterial thrombosis, blood vessel wall damage is required for thrombosis formation, as it initiates  coagulation , [ 26 ]  but the majority of venous thrombi form without any injured epithelium. [ 7 ]


Red blood cells  and  fibrin  are the main components of venous thrombi, [ 7 ]  and the thrombi appear to attach to the blood vessel wall  endothelium , normally a non-thrombogenic surface, with fibrin. [ 26 ]   Platelets  in venous thrombi attach to downstream fibrin, while in arterial thrombi, they compose the core. [ 26 ]  As a whole, platelets constitute less of venous thrombi when compared to arterial ones. [ 7 ]  The process is thought to be initiated by  tissue factor -affected thrombin production, which leads to fibrin deposition. [ 8 ]


The valves of veins are a recognized site of VT initiation. Due to the blood flow pattern, the base of the valve sinus is particularly deprived of oxygen ( hypoxic ). Stasis exacerbates hypoxia, and this state is linked to the activation of white blood cells ( leukocytes ) and the endothelium. Specifically, the two pathways of  hypoxia-inducible factor-1  (HIF-1) and  early growth response 1  (EGR-1) are activated by hypoxia, and they contribute to  monocyte  and endothelial activation. Hypoxia also causes  reactive oxygen species  (ROS) production that can activate HIF-1, EGR-1, and  nuclear factor-κB  (NF-κB), which regulates HIF-1 transcription. [ 8 ]


HIF-1 and EGR-1 pathways lead to monocyte association with endothelial proteins, such as  P-selectin , prompting monocytes to release tissue factor-filled  microvesicles , which presumably initiate fibrin deposition (via thrombin) after binding the endothelial surface. [ 8 ]


Numerous medications have been shown to reduce the risk of a person having a VTE, however careful decision making is required in order to decide if a person's risk of having a VTE outweighs the risks associated with most  thromboprophylaxis  treatment approaches (medications to prevent venous thrombosis).  It is recommended that people should be assessed at their hospital discharge for persistent high-risk of venous thrombosis and that people who adopt a heart-healthy lifestyle might lower their risk of venous thrombosis. [ 27 ]  Clinical policy from the American College of Physicians states a lack of support for any performance measures that incentivize physicians to apply universal prophylaxis without regard to the risks. [ 28 ]


Evidence supports the use of  heparin  in people following surgery who have a high risk of thrombosis to reduce the risk of DVTs; however, the effect on PEs or overall mortality is not known. [ 29 ]  In hospitalized non-surgical patients, mortality does not appear to change. [ 30 ] [ 31 ] [ 32 ]  It does not appear, however, to decrease the rate of symptomatic DVTs. [ 30 ]  Using both heparin and compression stockings appears better than either one alone in reducing the rate of DVT. [ 33 ]


In hospitalized people who have had a  stroke  and not had surgery, mechanical measures ( compression stockings ) resulted in skin damage and no clinical improvement. [ 30 ]  Data on the effectiveness of compression stockings among hospitalized non-surgical patients without stroke is scarce. [ 30 ]


The  American College of Physicians  (ACP) gave three strong recommendations with moderate quality evidence on VTE prevention in non-surgical patients:


In adults who have had their lower leg casted, braced, or otherwise immobilized for more than a week, LMWH may decrease the risk and severity of deep vein thrombosis, but does not have any effect on the incidence of  pulmonary embolism . [ 34 ]


Following the completion of warfarin in those with prior VTE, the use of long-term aspirin has been shown to be beneficial. [ 35 ]


People who have cancer have a higher risk of VTE and may respond differently to anticoagulant preventative treatments and prevention measures. [ 36 ]  The American Society of Hematology strongly suggests that people undergoing chemotherapy for cancer who are at low risk of a VTE avoid medications to prevent thrombosis ( thromboprophylaxis ). [ 37 ]  For people undergoing chemotherapy for cancer that do not require a hospital stay ( those undergoing ambulatory care ), there is low certainty evidence to suggest that treatment with  direct factor Xa inhibitors  may help prevent symptomatic VTEs, however this treatment approach may also lead to an increase in the risk of a major bleed compared to a  placebo  medication. [ 38 ]  There is stronger evidence to suggest that LMWH helps prevent symptomatic VTE, however this treatment approach also comes with a higher risk of a major bleed compared to a placebo medication or no treatments to prevent VTE. [ 38 ]


For people who are having surgery for cancer, it is recommended that they receive anticoagulation therapy (preferably LMWH) in order to prevent a VTE. [ 39 ]  LMWH is recommended for at least 7–10 days following cancer surgery, and for one month following surgery for people who have a high risk of VTEs. [ 40 ] [ 39 ]


Specifically for patients with various types of lymphoma, there is a risk assessment model,  ThroLy , to help providers determine how likely a thromboembolic event is to occur. [ 41 ]


American evidence-based clinical guidelines were published in 2016 for the treatment of VTE. [ 42 ]  In the UK, guidelines by the  National Institute for Health and Care Excellence  (NICE) were published in 2012, updated in 2020. [ 43 ]  These guidelines do not cover rare forms of thrombosis, for which an individualized approach is often needed. [ 5 ]  Central and branch retinal vein occlusion does not benefit from anticoagulation in the way that other venous thromboses do. [ 5 ]


If diagnostic testing cannot be performed swiftly, many are commenced on empirical treatment. [ 43 ]  Traditionally this was heparin, but several of the DOACs are licensed for treatment without initial heparin use. [ 42 ]


If heparin is used for initial treatment of VTE, fixed doses with  low-molecular-weight heparin  (LMWH) may be more effective than adjusted doses of  unfractionated heparin  (UFH) in reducing blood clots. [ 44 ]  No differences in mortality, prevention of major bleeding, or preventing VTEs from recurring were observed between LMWH and UFH. [ 45 ]  No differences have been detected in the route of administration of UFH ( subcutaneous  or  intravenous ). [ 44 ]  LMWH is usually administered by a  subcutaneous injection , and a person's blood clotting factors do not have to be monitored as closely as with UFH. [ 44 ]


Once the diagnosis is confirmed, a decision needs to be made about the nature of the ongoing treatment and its duration. USA recommendations for those without cancer include  anticoagulation  (medication that prevents further blood clots from forming) with the DOACs  dabigatran ,  rivaroxaban ,  apixaban , or  edoxaban  rather than  warfarin  or  low molecular weight heparin  (LMWH). [ 42 ]


For those with cancer, LMWH is recommended, [ 42 ]  although DOACs appear safe in the majority of situations. [ 43 ]  For long-term treatment in people with cancer, LMWH is probably more effective at reducing VTEs when compared to vitamin K antagonists. [ 36 ]  People with cancer have a higher risk of experiencing reoccurring VTE episodes ("recurrent VTE"), even while taking preventative anticoagulation medication. These people should be given therapeutic doses of LMWH medication, either by switching from another anticoagulant or by taking a higher dose of LMWH. [ 46 ]


In pregnancy, warfarin and DOACs are not considered suitable and LMWH is recommended. [ 42 ]


For those with a small pulmonary embolism and few risk factors, no anticoagulation is needed. [ 42 ]  Anticoagulation is, however, recommended in those who do have risk factors. [ 42 ]


Thrombolysis  is the administration of medication (a recombinant enzyme) that activates  plasmin , the body's main enzyme that breaks down blood clots. This carries a risk of bleeding and is therefore reserved for those who have a form of thrombosis that may cause major complications. In pulmonary embolism, this applies in situations where heart function is compromised due to lack of blood flow through the lungs ("massive" or "high risk" pulmonary embolism), leading to  low blood pressure . [ 42 ]  Deep vein thrombosis may require thrombolysis if there is a significant risk of  post-thrombotic syndrome . [ 42 ]  Thrombolysis may be administered by intravenous catheter directly into the clot ("catheter-directed thrombolysis"); this requires a lower dose of the medication and may carry a lower bleeding risk but evidence for its benefit is limited. [ 42 ]


Inferior vena cava filters  (IVCFs) are not recommended in those who are on anticoagulants. [ 42 ]  IVCFs may be used in clinical situations where a person has a high risk of experiencing a pulmonary embolism, but cannot be on anticoagulants due to a high risk of bleeding, or they have active bleeding. [ 46 ] [ 47 ]  Retrievable IVCFs are recommended if IVCFs must be used, and a plan should be created to remove the filter when it is no longer needed. [ 46 ]


While topical treatments for  superficial venous thrombosis  are widely used, the evidence is strongest for the heparin-like drug  fondaparinux  (a  factor Xa  inhibitor), which reduces extension and recurrence of  superficial venous thrombosis  as well as progression to symptomatic embolism. [ 48 ]


After an episode of unprovoked VTE, the risk of further episodes after completing treatment remains elevated, although this risk diminishes over time. Over ten years, 41% of men and 29% of women can expect to experience a further episode. For each episode, the risk of death is 4%. [ 49 ]


Virchow's triad  or the  triad of Virchow  ( / ˈ f ɪər k oʊ / ) describes the three broad categories of factors that are thought to contribute to  thrombosis . [ 1 ]


It is named after the renowned  German   physician   Rudolf Virchow  (1821–1902). However, the elements comprising Virchow's triad were not proposed by Virchow. Neither did he ever suggest a triad to describe the pathogenesis of venous thrombosis. In fact, it was not until decades after Virchow's death that a consensus was reached proposing that thrombosis is the result of alterations in blood flow, vascular endothelial injury, or alterations in the constitution of the blood. Still, the modern understanding of the factors leading to embolism is similar to the description provided by Virchow. Virchow's triad remains a useful concept for clinicians and pathologists alike in understanding the contributors to thrombosis. [ 3 ]


The triad consists of three components:


The origin of the term "Virchow's Triad" is of historical interest, and has been subject to reinterpretation in recent years. [ 7 ]  While both Virchow's and the modern triads describe  thrombosis , the previous triad has been characterized as "the consequences of thrombosis", and the modern triad as "the causes of thrombosis". [ 8 ]


Rudolf Virchow elucidated the etiology of  pulmonary embolism , whereby  thrombi  occurring within the  veins , particularly those of the extremities, become dislodged and migrate to the pulmonary vasculature. He published his description in 1856. [ 9 ]  In detailing the  pathophysiology  surrounding pulmonary embolism, he alluded to many of the factors known to contribute to venous thrombosis. While these factors had already been previously established in the medical literature by others, [ 10 ] [ 11 ]  for unclear reasons they ultimately became known as Virchow's triad. This  eponym  did not emerge in the literature until long after Virchow's death. One estimate of the first use of the phrase dates it to the early 1950s. [ 4 ]


Although the concept of the triad is usually attributed to Virchow, he did not include endothelial injury in his description. [ 12 ]  This has been attributed to a dispute Virchow had with  Jean Cruveilhier , who considered local trauma of primary importance in the development of pulmonary artery thrombosis. [ 13 ] [ 14 ]


A  welt  is a bloodshot stripe on the skin. They are  hematoma , a special form of a  bruise .


Welts occur when blunt force is applied to the body with elongated objects without sharp edges. Like other haematomas, welts change their colors as they heal, which usually takes two to four weeks. The colors include purplish black, reddish blue, brown or yellowish green. That makes it possible to determine their approximate age. [ 1 ]


A special form of welts—when the impact tool is not flat—are double welts. They occur after blows with stick-like, long objects, such as a cane for  caning , a  riding crop  or a  garden hose . The energy of the striking tool hitting the skin forces the tissue fluid or tissue matrix to the outside of the instrument. This leaves a rather anemic, brighter area of skin, so the area of impact of the striking tool on the skin is usually free of injury. [ 2 ]  However, capillary vessels located under the skin at the edges of the impacting object rupture, resulting in two parallel, striated skin lacerations. Such double straps in a child indicate abuse and require clarification. [ 3 ] [ 4 ] [ 5 ]


Alimentary toxic aleukia  is a  mycotoxin -induced condition characterized by  nausea , vomiting,  diarrhea ,  leukopenia  (aleukia),  hemorrhaging , skin inflammation, and sometimes death. [ 1 ]  Alimentary toxic aleukia almost always refers to the human condition associated with presence of  T-2 Toxin . [ 1 ]


Alimentary toxic aleukia manifests in inflammation of the  gastric  and  intestinal mucosa , a severe progressive  leukopenia ,  anemia , and an increased  erythrocyte sedimentation rate . Subsequently  petechial hemorrhages  of both the skin and  mucosa  as well as  enlarged lymph nodes  are seen. Symptoms of the respiratory system include  bronchopneumonia ,  pulmonary hemorrhages ,  sepsis , and  lung abscesses . Vomiting,  bloody stools ,  lassitude , and incoordination are also observed. [ 1 ]  The severity of the disease and its course was determined by the quantity of the  toxin  and the various reactive properties of various tissues and organs to the toxin. [ 2 ]


There are four stages of ATA. The first stage is acute intoxication. The  leukopenia  stage is the next. The third stage is distinguished by distinct clinical symptoms (anginal- hemorrhagic  stage), and the fourth by recovery and possible complications. [ 2 ]


Local and systemic symptoms can appear immediately or several hours after consuming a meal prepared with the toxic wintered grain. Local symptoms include a bitter taste in the mouth, which leads to a complete  loss of taste ,  tongue   numbness  or swelling, a burning sensation in the mouth, and pain when swallowing. If no more hazardous grain was consumed, the foregoing symptoms subsided within 2 or 3 days, but they resurfaced as soon as the patient resumed consumption of this grain. Toxemia manifested as  weakness ,  malaise ,  rheumatic -like pain,  hyperhidrosis , a condition similar to  alcohol intoxication , and  insomnia . These symptoms typically go away in 3 to 5 days. [ 2 ]


There were isolated cases of acute  food poisoning  resulting in acute  esophagitis ,  gastritis , or  gastroenteritis , with  hypersalivation ,  nausea , vomiting, esophageal and  stomach pain ,  diarrhea , and fevers of up to 39 degrees.  Giddiness , headache,  mydriasis ,  tachycardia ,  cyanosis , limb coldness, and  convulsions  were also reported. There were also  hemorrhagic diathesis  with cutaneous and  mucosal  hemorrhages and  epistaxis . In such circumstances, the blood count can indicate  hematopoiesis  alterations as quickly as 1-4 days; this was followed by  neutropenia  and relative  lymphocytosis ,  thrombocytopenia , and some  erythrocyte sedimentation rate  acceleration. [ 2 ]


With the subsequent ingesting of the toxic grain, the disease advances and enters the second stage within a few days. Because there is no habituation to the harmful substance, local symptoms may reoccur. The duration of the ATA leukopenia stage could vary from 2-3 weeks to 6-8 weeks and even 3-4 months. Clinically, the  leukopenia  stage manifests as symptoms of the  central  and  vegetative nervous systems . Patients reported  fatigue ,  apathy ,  vertigo , headache, and  poor sleep . The patients' skin would appear pale, and dry, and the symptoms of late dermographism  mydriasis  would be clearly visible. The patients showed a  petechial rash  towards the end of the  leukopenia  stage. The  petechial  patches were initially quite little, but as the disease advanced, they grew in size. When the  leukopenia  stage was treated promptly and adequately, it was often followed by recovery. [ 2 ]


Acute symptoms such as  rash ,  hemorrhages ,  necrotic   angina ,  high temperature , and  tachycardia  mark the third ATA stage. The  leukocyte  count continues to fall.  Bleeding time  increases, and the  coagulability  of the blood is delayed.  Hemorrhages  occur in the nose,  pharynx ,  esophagus , gut,  kidney ,  bladder , and  uterus .  Hemorrhages  can be severe and difficult to control, resulting in significant blood loss and even death. Patients develop  angina  several days following the formation of the petechial rash, which in severe cases might be necrotic or gangrenous. The tonsils completely decomposed, followed by acute edema of the  laryngeal vestibule  and blockage within 3-8 days with  necrotic  masses and  blood clots .  Asphyxia  and  aphonia  ensued, and many people died as a result. The  gangrenous  process progressed to the  soft palate , gums, tongue, lips, cheeks, and  nasal cavity , resulting in  tooth loss  and cheek perforation. These symptoms were particularly prevalent in individuals who had an imbalanced diet and in children. Severe  anginal  symptoms were followed by an increase in  hemorrhagic diathesis . Acute  hepatitis  typically manifests itself during the third ATA stage. The  liver  would become slightly enlarged, while the  spleen  would remain normal. There was  microhematuria  and, on rare occasions,  hematuria . Even in the most severe cases, significant improvements and even recovery within 1-2 weeks was feasible. Heart paralysis, uncontrollable  hemorrhages ,  suffocation ,  pneumonia  with pulmonary abscesses, and  gangrene  all contributed to death. [ 2 ]


When  pathogenetic  therapy was administered, the condition advanced to the fourth stage, which lasted 10-14 days. The  necrotic  fool began to mend and  hemorrhages  stopped during this pealed; a reduction of fever showed recovery from acute toxemia. However, lingering toxic symptoms ( tachycardia ,  hypotension , apical  systolic murmur , left heart dilatation,  dyspnea ,  weakness ,  vertigo ,  gastritis ,  gastroenteritis ,  hepatitis ,  central  and  vegetative nervous system  problems) persisted for an extended period of time. [ 2 ]


At the early stages of the condition, therapeutic measures include excluding various wintered grain products and flour from the diet and monitoring  erythrocyte ,  platelet , and  leukocyte  differential counts. In the second stage, therapeutic interventions include balanced nutrition, which includes biologically beneficial  proteins  and  Vitamins  such as  ascorbic acid ,  thiamine ,  riboflavin ,  niacin ,  vitamin B ,  folacin , and  vitamin E . [ 2 ]


When the condition reaches the third stage, the patient is immediately hospitalized and placed on a balanced diet. Early prescription or large doses of  sulfamide  compounds and adequate  antibiotics  were required, as well as the use of general and  hemopoiesis -stimulated  blood transfusion  and  autohemotherapy , the administration of  hemostatic , detoxicating, and  cardiovascular  activity-stimulating agents, and the local treatment of  necrotic  foci. [ 2 ]


In the fourth stage, medical treatments would be focused on increasing the body's response capacity through general bracing and  hemopoiesis  stimulation, as well as eradicating toxic residual effects with detoxication medications. [ 2 ]


Alimentary toxic aleukia was first characterized in the early 20th century after affecting a large population in the  Orenburg Oblast  of the former  USSR  in 1933 and during  World War II . The sick people had eaten overwintered grain colonized with  Fusarium sporotrichioides  and  Fusarium poae . [ 3 ]


Aplasia  ( / ə ˈ p l eɪ ʒ ə /   ⓘ ; from  Greek   a , "not", "no" +  plasis , "formation") is a  birth defect  where an  organ  or  tissue  is wholly or largely absent. It is caused by a defect in a developmental process. [ 1 ] [ 2 ]


Aplastic anemia  is the failure of the body to produce blood cells. It may occur at any time, and has multiple causes. [ 1 ] [ 2 ]


Pure red cell aplasia  (PRCA) is caused by the selective destruction or inhibition of  erythroid progenitor  or  precursor cells . It is characterized by  anemia  and  reticulocytopenia  and can be chronic or acute. [ 3 ]   Diamond–Blackfan anemia  is a type of PRCA that occurs at birth. PRCA can be acquired as a primary disorder or as a result of another disorder. [ 4 ]  Immunosuppressive drugs, particularly corticosteroids, will usually result in a temporary or permanent remission. The final outcome is primarily determined by the underlying disorder. [ 3 ]


Aplasia cutis congenita  is a condition in which some or large portions of the skin is missing at birth.  The disorder is most commonly seen on the scalp, often as a solitary lesion without other abnormalities. The condition may be caused by  epidermolysis bullosa , specific  teratogens , or  intrauterine infections , or it may be caused by  chromosomal abnormalities ,  ectodermal dysplasias , or other malformation syndromes. [ 5 ]


Radial aplasia  is a condition in which the  radius  does not form. The radius runs from your elbow to your wrist, where your thumb is located. With radial aplasia, the arm can look misshapen and bent. The thumb could also be absent or shorter than usual. [ 6 ]


Sertoli cell-only syndrome (SCOS), also known as germ cell aplasia, is defined by  azoospermia  where the testicular  seminiferous tubules  are lined solely with  sertoli cells . [ 7 ]   Sertoli cells  contribute to the formation of the  blood-testis barrier  and aid in sperm generation. These cells respond to  follicle-stimulating hormone , which is secreted by the  hypothalamus  and aids in  spermatogenesis . [ 8 ]
Men often learn they have Sertoli cell-only syndrome between the ages of 20 and 40 when they are checked for  infertility  and found to produce no sperm. Other signs and symptoms are uncommon, yet in some cases, an underlying cause of SCO syndrome, such as  Klinefelter syndrome , may produce other symptoms. [ 9 ]


Most cases of SCO syndrome are  idiopathic , however, causes may include deletions of genetic material on  Y-chromosome  regions, particularly the  azoospermia factor  area. Other factors include  chemical or toxin exposure , previous exposure to  radiation therapy , and a history of severe trauma. A testicular  biopsy  confirms the diagnosis of SCO syndrome. Although there is no effective treatment at the moment, assisted reproductive technology may help some men with SCO syndrome reproduce. [ 9 ]


Pulmonary aplasia is a rare congenital pathology characterized by the unilateral or bilateral absence of lung tissue. It is distinct from  pulmonary agenesis , which, while similar, has a short-blind ending  bronchus  in aplasia. Because bilateral pulmonary aplasia is not feasible, it is usually unilateral. It is frequently associated with other congenital abnormalities, primarily cardiovascular, and has been shown to occur with the  VACTERL syndrome .


Thymic aplasia is a rare  primary immunodeficiency  with autosomal or X-linked recessive inheritance, characterized by  thymus   atrophy  in the absence of other congenital abnormalities, profound  T-cell deficiency , and normal or increased serum  immunoglobulin  levels. Patients present with chronic or recurring infections in infancy, such as  candidiasis , skin, pulmonary, and  urinary tract infections ,  chronic diarrhea , and  failure to thrive . [ 10 ]


Optic nerve aplasia (ONA) is a congenital  optic nerve  anomaly defined as the absence of the  optic nerve head , the  retinal  blood vessels,  ganglion cells of the retina , and optic  nerve fibers  in an otherwise normal eye. Clinically, the condition is characterized by a lack of  light perception , an  afferent pupillary defect , and a  fundus  appearance of an absent optic nerve head and retinal vessels, as well as other ocular and nonocular abnormalities. Bilateral ONA has been linked to systemic anomalies, whereas unilateral ONA is seen in otherwise healthy people. [ 11 ]


Aplastic anemia  is a  bone marrow failure  syndrome characterized by peripheral  pancytopenia  and  bone marrow  hypoplasia. Although the  anemia  is usually  normocytic , mild  macrocytosis  can be seen in conjunction with stress  erythropoiesis  and raised  fetal hemoglobin  levels. Aplastic anemia patients present with symptoms related to a decrease in  hematopoietic cell  production in the  bone marrow . The onset is gradual, and the first symptom is frequently  anemia  or bleeding, though a  high temperature  or  infections  may be present at the onset. The following are examples of specific manifestations: [ 12 ]


The majority of cases of aplastic anemia are idiopathic, and seeking a possible cause is frequently unproductive. [ 12 ]


Aplasia is a rare condition.  Radial aplasia  and  pure red cell aplasia , particularly the acquired form of pure red cell aplasia, are the most common types. Radial aplasia affects about one in every 30,000 newborns. Radial ray deficiencies, such as radial aplasia, are one of the most common congenital arm disabilities. Congenital pure red cell aplasia is uncommon, with an estimated 5 to 7 cases per million births. The acquired form is more prevalent. [ 6 ]


Atypical hemolytic uremic syndrome  ( aHUS ), also known as  complement-mediated   hemolytic   uremic   syndrome  (not to be confused with  hemolytic–uremic syndrome ), is an extremely  rare , life-threatening,  progressive disease  that frequently has a  genetic component . In most cases, it can be effectively controlled by interruption of the complement cascade. Particular  monoclonal antibodies , discussed later in the article, have proven efficacy in many cases.


aHUS is usually caused by chronic, uncontrolled activation of the  complement system , [ 1 ] [ 2 ]  a branch of the body's immune system that destroys and removes foreign particles. [ 3 ]  The disease affects both children and adults and is characterized by systemic  thrombotic microangiopathy (TMA) , the formation of  blood clots  in  small blood vessels  throughout the body, which can lead to  stroke ,  heart attack , kidney failure, and death. [ 1 ] [ 4 ] [ 5 ]  The complement system activation may be due to mutations in the complement regulatory proteins ( factor H ,  factor I , or  membrane cofactor protein (CD46) ), [ 6 ] [ 5 ] [ 7 ]  or occasionally due to acquired neutralizing autoantibody inhibitors of these complement system components (e.g.  anti–factor H antibodies ). [ 8 ] : 1933   Prior to availability of  eculizumab (Soliris)  and  ravulizumab (Ultomiris) , an estimated 33–40% of patients developed  end-stage renal disease (ESRD)  or died (despite the use of supportive care, e.g.  plasmapheresis ) with the first clinical bout of aHUS. Including subsequent relapses, a total of approximately two-thirds (65%) of patients required  dialysis , had permanent renal damage, or died within the first year after diagnosis despite  plasma exchange or plasma infusion (PE/PI) . [ 7 ]


Clinical signs and symptoms of complement-mediated TMA can include abdominal pain, [ 9 ]   confusion , [ 9 ]   fatigue , [ 5 ]   edema (swelling) , [ 10 ]  nausea/vomiting [ 11 ]  and diarrhea. [ 12 ]   aHUS often presents with  malaise  and fatigue, as well as microangiopathic anemia. [ 8 ] : 1931   However, severe abdominal pain and  bloody diarrhea  are unusual. [ 8 ] : 1931    Laboratory tests may also reveal low levels of platelets (cells in the blood that aid in clotting), [ 1 ]  elevated  lactate dehydrogenase  (LDH, a chemical released from damaged cells, and which is therefore a marker of  cellular damage ), [ 7 ]  decreased  haptoglobin  (indicative of the breakdown of red blood cells), [ 7 ]  anemia (low red blood cell count)/schistocytes (damaged red blood cells), [ 1 ] [ 7 ]  elevated creatinine (indicative of kidney dysfunction), [ 13 ]  and proteinuria (indicative of kidney injury). [ 14 ]  Patients with aHUS often present with an abrupt onset of systemic signs and symptoms such as acute kidney failure, [ 1 ]  hypertension (high blood pressure), [ 5 ]  myocardial infarction (heart attack), [ 15 ]  stroke, [ 9 ]  lung complications, [ 15 ]  pancreatitis (inflammation of the pancreas), [ 11 ]  liver necrosis (death of liver cells or tissue), [ 5 ]  encephalopathy (brain dysfunction), [ 5 ]  seizure, [ 16 ]  or coma. [ 17 ]  Failure of neurologic, cardiac, kidney, and gastrointestinal (GI) organs, as well as death, can occur unpredictably at any time, either very quickly or following prolonged symptomatic or asymptomatic disease progression. [ 1 ] [ 14 ] [ 18 ] [ 19 ] [ 20 ]  For example, approximately 1 in 6 patients with aHUS will initially present with proteinuria or hematuria without acute kidney failure. [ 14 ]  Patients who survive the presenting signs and symptoms endure a chronic thrombotic and inflammatory state, which puts many of them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death. [ 10 ] [ 21 ]


Although many patients experience aHUS as a single disease, comorbidities are common. In one study, 25% (47/191) of patients with no known family history of aHUS were found to have a coexisting disease or condition. Comorbidities in this study included malignant hypertension (30%), TMA with a history of transplant (23%), TMA associated with pregnancy (21%),  glomerulopathy  (17%), systemic disease such as  systemic lupus erythematosus (SLE)  or  progressive systemic sclerosis (PSS)  (6%), and malignancy (1%). [ 5 ]  The presence of mutations in complement regulatory proteins, or of disease-associated variations in the genes encoding these proteins (i.e., in most patients with comorbid conditions as well as in patients with aHUS as a single disease), suggests that deviations from the normal genetic coding of these factors could result in a genetic predisposition to TMA. Individuals so predisposed could have aHUS episodes precipitated by one of the known disease triggers (e.g., infection, pregnancy, surgery, trauma) as well as by other systemic diseases (e.g., malignant hypertension, SLE, cancer). [ citation needed ]


In healthy individuals, complement is used to attack foreign substances, and the complement system is highly regulated to prevent it from damaging healthy tissues and organs. [ 1 ] [ 18 ]  However, in most patients with aHUS, it has been demonstrated that chronic, uncontrolled, and excessive activation of complement can result from production of anti-factor H autoantibodies or from genetic mutations in any of several complement regulatory proteins (e.g., factor H, factor HR1 or HR3, membrane cofactor protein, factor I, factor B, complement C3, and  thrombomodulin ). [ 18 ]  This results in platelet activation, damage to  endothelial cells  (cells that line the blood vessels), and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count,  hemolysis  (breakdown of red blood cells), damage to multiple organs, and often, death. [ 14 ] [ 19 ] [ 22 ]


aHUS is not the only condition that causes systemic TMA, a fact that makes differential diagnosis essential. Historically, the clinical diagnosis of TMA-causing diseases was grouped into a broad category that (in addition to aHUS) included  thrombotic thrombocytopenic purpura  (TTP) and Shiga-toxin-producing Escherichia coli hemolytic uremic syndrome ( STEC-HUS ). [ 19 ] [ 21 ]  However, it is now understood that although aHUS, STEC-HUS, and TTP have similar clinical presentations, they have distinct causes and specific tests can be conducted to differentiate these diseases. In addition, there are other conditions that can cause TMA as a secondary manifestation; these entities include systemic lupus erythematosus (SLE), malignant hypertension, progressive systemic sclerosis (PSS, also known as scleroderma), pregnancy-associated HELLP (hemolysis, liver dysfunction, and low platelets) syndrome, and toxic drug reactions (e.g., to cocaine, cyclosporine, or tacrolimus). Nevertheless, aHUS should be suspected in patients presenting with systemic TMA, and appropriate diagnostic work-up should be undertaken. [ citation needed ]


The neurological and kidney-related signs and symptoms of aHUS overlap with those of TTP. [ 13 ] [ 23 ]  However, unlike aHUS, TTP is primarily an autoimmune disorder in which the presence of an inhibitory autoantibody results in severe deficiency of  ADAMTS13 , an enzyme that cleaves von Willebrand factor (vWF, a large protein involved in blood clotting) into smaller pieces. [ 22 ]  TTP also can be a genetic disorder characterized by mutations in the ADAMTS13 gene leading to severe ADAMTS13 deficiency. This congenital cause of ADAMTS13 deficiency is called  Upshaw-Schulman syndrome . [ 24 ] ) A lab test showing ADAMTS13 activity levels of ≤5% is indicative of TTP. [ 22 ]


Similarly, the gastrointestinal (GI) signs and symptoms of aHUS overlap with those of STEC-HUS. [ 12 ] [ 25 ] [ 26 ]  Stool samples from patients with diarrhea or other GI symptoms should be tested for STEC and the presence of Shiga-toxin. However, a positive identification of Shiga-toxin, which is required to diagnose STEC-HUS, does not rule out aHUS. Nevertheless, in the appropriate clinical setting, a positive identification of Shiga-toxin makes aHUS very unlikely. [ 13 ] [ 26 ]


aHUS patients report a mean timeline of 29 days for the overall diagnosis process from first noticing symptoms to receiving an aHUS diagnosis. During this time, they report an overall health state drop – from 88% of patients falling between good and excellent, to 99% falling between good and very poor – and a decrease in health status index by more than half – from 3.8 (on a scale of 1 to 5) pre-illness, to 1.4 at diagnosis. [ 27 ]