Although plasma exchange/infusion (PE/PI) is frequently used, there are no controlled trials of its safety or efficacy in aHUS. Even though PE/PI often partially controls some of the hematological manifestations of aHUS in some patients, its effectiveness has not been demonstrated in terms of inducing total disease remission.  PE/PI is associated with significant safety risks, including risk of infection, allergic reactions, thrombosis, loss of vascular access, and poor quality of life. [ 23 ] [ 28 ]  Importantly, terminal complement activation has been shown to be chronically present on the surface of platelets in patients with aHUS who appear to be clinically well while receiving chronic PE/PI. [ 10 ] [ 29 ]


Guidelines issued by the European Paediatric Study Group for HUS recommend rapid administration of  plasma exchange  or  plasma infusion  (PE/PI), intensively administered daily for 5 days and then with reducing frequency. [ 23 ]  However, the American Society for Apheresis offers a "weak" recommendation for plasma exchange to treat aHUS, due to the "low" or "very low" quality of evidence supporting its use. Although some patients experienced improvements in red blood cell and platelet counts, plasma therapies generally did not result in full remission. [ 30 ]


Eculizumab (Soliris)  appears to be useful for atypical hemolytic uremic syndrome (aHUS). [ 31 ]  In September 2011 the  U.S. Food and Drug Administration  (FDA) approved it as an  orphan drug  to treat people with aHUS. [ 32 ]  This approval was based on two small prospective trials of 17 people and 20 people. [ 31 ]  In the UK,  NICE  issued guidance on the use of Eculizumab for treating aHUS, based on five evidence sources, including those used by the FDA [ 33 ]  No randomised controlled trials were identified. All prospective studies were phase 2, open‑label, non‑randomised, single‑arm studies that included patients with different clinical baseline characteristics. The prospective studies lasted 26 weeks; however, patients were allowed to continue treatment with eculizumab in a long‑term extension study. [ citation needed ]


Ravulizumab-cwvz (Ultomiris) is a second generation monoclonal antibody for aHUS made by Alexion pharmaceuticals, Inc. [ 34 ]  The target of ravulizumab-cwvz is the same eculizumab (Soliris) with changes to the structure of the antibody resulting in a longer serum half life and therefore reduced dosing regimen. [ 35 ]


Patients with aHUS who have ESRD are generally consigned to lifelong dialysis, which carries a 5-year survival rate of 34–38%, [ 36 ] [ 37 ]  with infections accounting for 14% of deaths. [ 38 ]  These patients also remain at ongoing risk of non-kidney systemic complications of the disease. [ citation needed ]


Despite its history of use in patients with aHUS, kidney transplantation does not address the continued and uncontrolled complement activation that leads to progressive, systemic TMA. As many as 90% of patients with aHUS and who are not treated with Soliris or Ultomiris, experience TMA in the transplanted organ, leading to transplant failure. [ 12 ] [ 39 ]  Patients who have undergone kidney transplantation are still at continued risk of neurological, gastrointestinal, and cardiovascular complications and, importantly, premature mortality. Following kidney transplantation, the ongoing, uncontrolled, chronic complement activation associated with aHUS causes graft loss in 66% of children and 55% of adults, as well as continued inflammatory and TMA insult to other organs. [ 1 ] [ 5 ]  Combined liver-kidney transplantation is only available to very few patients, due to the limited supply of solid organs. In addition, there is a substantial near-term risk of mortality, which many physicians and patients consider excessive. [ 1 ]  In recent years, some transplant centers have begun to administer eculizumab to patients with TMA who receive a kidney transplant. This strategy has been effective in preventing TMA recurrences in these patients. [ 40 ]


Patients using either eculizumab or ravulizumab for the treatment of aHUS showed improvements in kidney function even avoiding dialysis and minimizing death. Markers of disease activity in the blood also had a great improvement. However, the only available evidence has substantial bias and low quality and therefore there should be careful considerations for futures studies in treatment duration, adverse outcomes and risk of disease recurrence associated with this treatment. [ 41 ]


Prior to the use of monoclonal antibodies(e.g., Soliris, Ultomiris) patients with aHUS had an extremely poor prognosis. Among those with the most commonly identified aHUS genetic mutation, the proportion of patients experiencing negative outcomes (e.g., need for dialysis, permanent kidney damage, death) within the first year rose to 70%. [ 7 ]  However, sudden morbidity and mortality could occur regardless of mutational status. aHUS can arise at any age, with more than 40% of cases first reported after 18 years of age. [ 5 ]  The oldest presentation in one study was at age 83. [ 5 ]  As noted above, kidney transplantation for aHUS patients with ESRD was rarely considered because of a high incidence of graft loss due to TMA recurrence in the transplanted organ in up to 90% of patients. [ 12 ] [ 39 ]  Consequently, most untreated aHUS patients develop ESRD and undergo chronic dialysis, which is associated with significant morbidities and worsened prognosis. [ 12 ]  Combined liver-kidney transplantation has been attempted in patients with aHUS, although this high-risk procedure has a mortality rate approaching 50%. [ 42 ]


Prior to availability and usage of the treatments,  quality of life was very poor for patients with aHUS; burdened with fatigue, renal complications, hypertension, neurological impairment, gastrointestinal distress, clotting at the site of venous access, and in worst cases, death. [ 7 ]  PE/PI is also reported to be associated with significant safety risks and is highly disruptive to patients' lives due to the requirements for extensive vascular access and frequent administration. [ 13 ] [ 43 ]


Since the approval of eculizumab (Soliris) the prognosis for aHUS patients has improved greatly. [ 44 ]  Risk of relapse is present after discontinuation of eculizumab treatment and close monitoring is required. [ 44 ]


aHUS can be inherited or acquired, and does not appear to vary by race, gender, or geographic area. [ 18 ]  As expected with an ultra-rare disease, data on the prevalence of aHUS are extremely limited. A pediatric prevalence of 3.3 cases per million population is documented in one publication of a European hemolytic uremic syndrome (HUS) registry involving 167 pediatric patients. [ 45 ]  Of aHUS cases, approximately 60 percent have genetically inherited aHUS. [ 46 ]


Atypical hemolytic uremic syndrome (aHUS) has also been referred to as diarrhea-negative  hemolytic-uremic syndrome  (D −  HUS). [ 47 ] : 2170


Patient advocacy groups have been helping to determine research priorities. [ 48 ]


The  blood hammer  phenomenon is a sudden increase of the upstream  blood pressure  in a  blood vessel  (especially  artery  or  arteriole ) when the  bloodstream  is abruptly blocked by vessel obstruction. The term "blood-hammer" was introduced in  cerebral   hemodynamics [ 1 ] [ 2 ]  by analogy with the  hydraulic  expression " water hammer ", already used in  vascular   physiology  to designate an arterial pulse variety, the " water-hammer pulse ". Complete understanding of the relationship between mechanical parameters in vascular occlusions is a critical issue, which can play an important role in the future diagnosis, understanding and treatment of vascular diseases.


If the time of shock wave propagation caused by the blood encountering an obstacle is equal to or less than the semilunar valve closure time, this can create a partial blood hammer phenomenon where flow speed oscillation increases without an accompanying abnormal pressure increase, whereas patients without a prolonged aortic valve closure time have the kinetic energy associated with turning around after an obstruction into a pressure peak, with little energy dedicated to increasing flow speed oscillations in a complete blood hammer effect. Flow leakage is also possible in an incomplete blood hammer, which is not seen in the complete blood hammer effect. [ 3 ]


Blood vessel disorder  generally refers to the narrowing, hardening or enlargement of  arteries  and  veins . It is often due to the build-up of fatty deposits in the  lumen  of blood vessels or infection of the vessel wall. This can occur in various locations such as coronary blood vessels, peripheral arteries and veins. The narrowed arteries would block the blood supply to different organs and tissues. [ 1 ]  In severe conditions, it may develop into more critical health problems like  myocardial infarction ,  stroke  or  heart failure , which are some of the major reasons of death. [ 2 ]


There are many causes contributing to blood vessel disorder including high blood  cholesterol  and calcium levels, blood clot formation and inflammation of arteries. It is found that age, sedentary lifestyle, diets rich in lipids, smoking,  diabetes  and family history of  cardiovascular diseases  are common risk factors. [ 3 ]  A mild degree of blood vessel disorder may be asymptomatic. [ 4 ]  Blood tests on cholesterol and calcium level can be performed to monitor the risk of having the disorder. Additionally, techniques such as  angiography  and  ultrasound  imaging are useful tools for diagnosis. [ 5 ]  It can be treated by both medication or surgery, depending on the type of blood vessel disorder. [ citation needed ]


Atherosclerosis  is a developmental disease in the large arteries, defined by the accumulation of lipids, macrophages and fibrous materials in the intima. [ 1 ]  When the endothelial cell of blood vessel is damaged, it loses the ability to regulate itself. [ 1 ]  It results in inflammation as the  macrophages  irrupt the vessel wall. [ 1 ]  Macrophages take up lipoprotein to form foam cells and release growth factor  cytokines  to attract more macrophages and smooth muscle cells. [ 1 ]  A plaque is formed and proliferate to a larger size, gradually occluding the blood flow. [ 1 ]  More importantly, it causes different complications that affect the whole body. [ 1 ]


An  aneurysm  is a localized enlargement of arteries, characterized by a balloon-like bulge. [ 6 ]  It results from the abnormal weakening of blood vessel wall. [ 7 ]  Common types of aneurysm include  abdominal aortic aneurysm ,  thoracic aortic aneurysm  and  intracranial aneurysm . [ 7 ]  Most types of aneurysm, except intracranial aneurysm, are mainly caused by atherosclerosis. [ 7 ]


Raynaud’s disease  is a rare peripheral vascular syndrome that narrows blood vessels, generally in the hands and feet, due to cold or stressful emotion. [ 8 ]  It is recognized by the reduction of blood flow to fingers and toes with periodic spasm and results in a drastic color change to white or blue. [ 8 ] [ 9 ]  The disease may further develop into ischaemic pain and  necrosis  of fingers or toes. [ 9 ]  The pathology of Raynaud's disease starts with the activation of sympathetic nervous system triggered by cold or the feeling of stress. [ 8 ]


Venous thromboembolism  (VTE) is a common peripheral venous disease. It is defined by the occlusion of venous blood vessels by blood clots. There are two major types of VTE: deep-vein thrombosis (DVT) and pulmonary embolism. [ 10 ]  DVT is often found in the calf, accompanies with the swelling of limbs along the deep vein while  pulmonary embolism  causes chronic  pulmonary hypertension . [ 11 ]  VTE is the third deadliest cardiovascular disease in the world. [ 11 ]   Haemostasis  is the rapid development of blood clots for the purpose of reducing blood loss. [ 11 ]  On the contrary, venous clots are formed much slower, in terms of several days or even weeks. Abnormality of coagulation during haemostasis, change in blood flow and endothelial failure may trigger VTE. [ 11 ]


Erythromelalgia  is a rare clinical disorder causing redness, burning sensation and intense pain in limbs. [ 12 ]  It is more common to be found in lower limbs than upper limbs. [ 12 ]  Erythromelalgia initiated from dysfunction of peripheral nerves that thickens the blood vessel walls, resulting in hyperaemic flow in limbs. [ 13 ]


Stroke  is a serious condition of blood vessel disorder caused by the stop of blood supply to the brain. Brain cells with ceased oxygen supply from blood will die in millions per second. [ 14 ]  Not only is it one of the major causes of death around the world, it is also the cause of permanent disability. Two major types of stroke include ischemic stroke which is caused by atherosclerosis in the brain and hemorrhagic stroke which is the bleeding in the brain due to weakened blood vessel wall inside the brain. [ citation needed ]


It is often asymptomatic in the early stages of blood vessel disorder. [ 4 ]  When the disease develops, a variety of signs can be observed in different body parts. For instance, patients may have pale skin, cold hands and feet, and numb fingertips. These are mainly due to the reduction in blood flow to the limbs, resulting in a decrease in heat distribution to these areas.  Ulcers  and wounds would also take a much longer time to heal because of the impairment in  blood clot formation  process. Muscle weakness and cramping may occur as well, especially in the legs, because of the insufficient oxygen supply to muscle cells for metabolism. [ citation needed ]


The vascular system strongly influences the condition of the heart. It is also vital in the rest of the body as the blood vessels are in charge of carrying nutrients and the discard of metabolic wastes. Therefore, blood vessel disorder can cause serious complications in the whole body. [ citation needed ]


Coronary arteries  are the blood vessels that supply to the heart for its normal function. Blood vessel disorders occur in coronary arteries would affect cardiac activity. For instance, due to atherosclerosis, the plaque would obstruct and causes  ischaemia  - the reduction of blood flow through the arteries. Ischaemia would then result in the decrease in oxygen supply to the heart, hence weaken the heart. It causes a vicious cycle as a weakened heart contraction would decrease blood supply to the body, including  cardiac muscle  (muscle of heart). Moreover, if the plaque suddenly ruptures in the heart, it will cause a  heart attack . [ citation needed ]


Various factors may affect one's susceptibility to blood vessel disorders, including behavioural (e.g. smoking), demographic (e.g. age) and genetic (family history) factors. Most of these risk factors first promote the increase in blood pressure, followed by other symptoms and signs. [ citation needed ]


The rise of blood pressure is correlated to ageing. [ 3 ]  The arterial  compliance  - the amount of tension produced per stretch of arteries, decreases with age, and the stiffness of arteries increases with age. [ 3 ]  The structural change in blood vessels causes the elderly to be more susceptible to hypertension, which leads to complications in arteries, the heart and even the brain. [ citation needed ]


Having  obesity  would increase the risk of atherosclerosis. [ 1 ]  A high-fat and high-cholesterol diet would result in an elevation of lipoprotein level, which is one of the constituents of plaque. Lipoprotein level above > 25–30 mg/dl is considered more susceptible by blood vessel disorders. [ 1 ]


Some of the blood vessel disorders are inherited. For instance, erythromelalgia is caused by the mutation of the SCN9A gene, which alters the neural pathway to blood vessels. [ 8 ]  Genetic disorders that affect the circulatory, immune or neural system may contribute to hereditary blood vessel disorder. If one’s family history shows records of vascular disorders, it is more likely to inherit the same disease. [ citation needed ]


Both  active  or  passive  smoking may bring harm to the vascular system. [ 15 ]  For instance, cigarette smoking,  cannabinoids  and smokeless tobacco use were all found to raise blood pressure and increase the risk of stroke. [ 15 ]  Moreover, cigar and cigarette smoking may also cause arterial stiffness. [ 15 ]


Some medications may have the side effect of increasing blood pressure and may even suppress the effect of anti-inflammatory drugs. Pain and anti-inflammatory drugs like  Indomethacin ,  nonsteroidal anti-inflammatory drugs  and  piroxicam  would retain water in the systemic circulation, raising the blood pressure. [ 16 ]  Other types of medications like antidepressant, hormone and caffeine would also increase blood pressure. [ citation needed ]


Doctors may look for signs of narrowed, enlarged or hardened arteries by performing a physical examination. [ 17 ]  If blood vessel disorder is present, there will be a weak or even absent pulse under the narrowed area of the artery. The blood pressure in the affected limb would be lowered and whooshing sounds can be heard over the affected arteries using a  stethoscope . [ 17 ]  After that, the following tests could be adapted to further locate the point of narrowing or enlargement of blood vessels. [ citation needed ]


Angiography is a medical imaging technique used to visualize the lumen of blood vessels. [ 18 ]  A  catheter , which is a long and thin tube, is inserted into a large artery in the arm or groin area. It is then guided along the artery to the targeted blood vessel to be examined. An imaging dye is loaded into the blood vessel through the catheter and the movement of the dye in the blood vessel is recorded as an angiogram. [ 18 ]  Doctors could determine if there are any abnormalities in the blood vessel using  fluoroscopy ,  computed tomography (CT) angiography  or  magnetic resonance (MR) angiography . After the catheter is removed, some pressure is applied to the incision site for 10 to 20 minutes to prevent excessive bleeding. [ citation needed ]


Vascular ultrasound is a non-invasive imaging method to examine the circulation inside blood vessels. Sound waves are transmitted through the tissues of the targeted area and they reflect on the blood cells moving within blood vessels. [ 19 ]  The waves recorded are displayed as an image of the blood vessel and the speed of waves detected can be used to calculate the speed of blood flow inside the vessel. [ 20 ]  When the rate of blood flow is too low, there may be a blockage of vessel. By evaluating blood flow in vessels, the severity and specific location of blood vessel disorder can be determined. [ 20 ]


Different kinds of treatment should be adopted according to the type and severity of blood vessel disorder. Medications are usually prescribed to relieve specific symptoms arisen from the disease while surgery like angioplasty can be performed to provide a more long-lasting effect. [ citation needed ]


Angioplasty  is a procedure used to widen narrowed blood vessels, especially in coronary arteries. A long and thin tube called catheter is inserted into a large artery through an incision in the wrist, arm or groin area. The catheter is guided to the affected artery using a real-time x-ray video. A thin wire is then introduced into the blood vessel, delivering a small balloon to the affected area. The balloon is inflated to stretch the blood vessel and compress the fatty deposits against the wall of artery. [ 21 ]  Hence, the vessel is widened and blood can flow through it freely to maintain adequate blood supply to different tissues. Finally, the balloon is deflated and removed. A stent may also be placed to provide support to the vessel wall and prevent it from re-narrowing. [ 22 ]


Beta blockers  are medications that inhibit the sympathetic nervous system by blocking the beta  adrenergic receptors . They can be used to slow down heart rate and decrease blood pressure by inhibiting beta receptors in the heart. [ 23 ]  These medications also induce vasodilation by relaxing smooth muscle in blood vessels. Examples of beta blockers include  carvedilol ,  metoprolol , and  bisoprolol .  [ citation needed ]


Calcium channel blockers  are medications that prevent the movement of calcium ions across calcium channels. They can be used to relieve hypertension by causing vascular smooth muscle relaxation. [ 24 ]  They also reduce the heart rate and contractility to lower the cardiac output, which in turn lower blood pressure.  Amlodipine ,  hydralazine  and  dihydropyridine  are examples of calcium channel blockers. [ citation needed ]


Other medications such as  angiotensin-converting enzyme  (ACE) inhibitors and diuretics can be used to relieve hypertension. [ 25 ]   Statins  and  fibrates  can also be prescribed to lower blood cholesterol level and hence reducing the risk of plaque formation in blood vessels. [ 26 ]  Anti-platelet medications e.g.  aspirin  help reducing blood clot formation in vessels as well.


The  Fugates , commonly known as the " Blue Fugates " [ 1 ]  or the " Blue People of Kentucky ", are an ancestral family living in the hills of  Kentucky  starting in the 19th century, where they are known for having a  genetic trait  that led to the  blood disorder   methemoglobinemia , causing the skin to appear blue.


Martin Fugate and Elizabeth Smith, [ 2 ]  who had married and settled near  Hazard, Kentucky , in around 1820, were both carriers of the  recessive  methemoglobinemia (met-H) gene. As a result, four of their nine children exhibited blue skin. Their continued reproduction within the limited local gene pool along with a lack of transportation infrastructure ensured that many descendants of the Fugates were born with met-H. [ 3 ] [ 4 ] [ 5 ]


The disorder can cause heart abnormalities and seizures if the amount of methemoglobin in the blood exceeds 20 percent, but at levels between 10 and 20 percent it can cause blue skin without other symptoms. Most of the Fugates lived long and healthy lives. The "bluest" of the blue Fugates, Luna Stacy, had 13 children and lived to age 84. [ 6 ]


Descendants with the gene continued to live near  Troublesome Creek  and Ball Creek into the 20th century. They eventually came to the attention of the  hematologist  Madison Cawein III, who with the assistance of the nurse Ruth Pendergrass made a detailed study of their condition and ancestry. [ 2 ] [ 7 ]  Based on a report published in the  Journal of Clinical Investigation  in 1960 by a public health physician named E. M. Scott, who had studied a similar phenomenon among  native Alaskans , Cawein concluded that a deficiency of the  enzyme   diaphorase  resulted in an oxygen deficiency in the red blood cells, causing the blood to appear brown, which in turn made the skin of those affected appear blue. [ 5 ]  He treated the family with  methylene blue , which eased their symptoms and reduced the blue coloring of their skin. [ 8 ]  His findings were published in the  Archives of Internal Medicine  in 1964. [ 9 ]


Benjamin Stacy, born in 1975, was the last known descendant of the Fugates to have been born exhibiting the characteristic blue color of the disorder, though he quickly lost his blue skin tone, exhibiting only blue tinges on his lips and fingertips when he became cold or agitated. [ 5 ]


In 2019, the novel  The Book Woman of Troublesome Creek , by  Kim Michele Richardson , described a fictional version of the Fugate family during the  Great Depression .


In 2021, the novel  Blue-Skinned Gods  by  S. J. Sindu  references a family from Kentucky with  methemoglobinemia  but does not use the surname Fugate.


A reference to "the Huntsville subgroup" is made in the American version of television sitcom  Shameless  when  Kevin Ball  (played by  Steve Howey ) discovers that he may have ancestors from that group. [ 10 ]


Cytopenia  is a reduction in the number of mature  blood cells . It can have many causes, and commonly occurs in people with cancer being treated with  radiation therapy  or  chemotherapy .


There are also two general causes of cytopenia: autoimmune and refractory. Autoimmune cytopenia is caused by an autoimmune disease when your body produces antibodies to destroy the healthy blood cells. Refractory cytopenia is caused by bone marrow not producing healthy blood cells, and can be a result of cancer.


The symptoms of cytopenia vary depending on the type.


The symptoms of anemia include: [ citation needed ]


The symptoms of leukopenia include:


The symptoms of thrombocytopenia include:


Cytopenias can be caused by anything that decreases the production of blood cells or increases the destruction of blood cells. This includes, but is not limited to: [ citation needed ]


The treatments for cytopenia vary depending on the type of cytopenia. The treatment for anemia is rest and a diet consisting of high iron foods. Medication can also be used such as: [ citation needed ]


People with thrombocytopenia are advised to avoid contact with people who are ill, monitor closely for signs of infection, and take antibiotics when appropriate.


Bone marrow and stem cell transplantation are effective for all types of cytopenias. However, when a compatible donor cannot be found,  immunosuppressive therapy  is also common.  Antilymphocyte globulin  (ALG) or  antithymocyte globulin  (ATG) is mixed with  cyclosporine  to promote cell growth.  [ 5 ]


Primary  fibrinogenolysis  is a  medical condition  that appears with abnormal production of  fibrinogen/fibrin degradation products  (FDP), degradation of  coagulation  factors V, VIII, IX, XI and/or degradation of the  fibrin  present in any pre-existing localized  thrombi  and  hemostatic  clots. [ 1 ] [ 2 ]


There are many conditions of or affecting the human  hematologic system —the  biological system  that includes  plasma ,  platelets ,  leukocytes , and  erythrocytes , the major components of blood and the  bone marrow . [ 1 ]


An  anemia  is a decrease in number of  red blood cells  (RBCs) or less than the normal quantity of  hemoglobin  in the blood. [ 2 ] [ 3 ]  However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of  hemoglobin deficiency . [ citation needed ]


Anemia is the most common disorder of the blood. There are several kinds of anemia, produced by a variety of underlying causes. Anemia can be classified in a variety of ways, based on the morphology of RBCs, underlying etiologic mechanisms, and discernible clinical spectra, to mention a few. The three main classes of anemia include excessive blood loss (acutely such as a  hemorrhage  or chronically through low-volume loss), excessive blood cell destruction ( hemolysis ) or deficient red blood cell production (ineffective  hematopoiesis ). Based on 2005-2006 estimates, the  Centers for Disease Control and Prevention  has stated that approximately 5.5 million Americans a year are either admitted to a hospital or seen by a physician, with some form of anemia as their primary diagnosis. [ 4 ]


Symptoms of anaemia include Plummer–Vinson syndrome, candidal infections. Altered taste sensation, smooth, red painful burning sensation of tongue, filiform followed by fungiform papillae atrophy may also be seen. Others include generalized stomatitis, angular cheilitis and gingivitis. [ citation needed ]


Oral manifestation of anemia include angular cheilitis, generalized stomatitis, candidiasis and gingivitis. There will be pallor of lips and oral mucosa. Patients might have a smooth, red painful tongue, experience burning sensation of tongue or disturbed taste sensation. Atrophy of filiform and fungiform papillae may also occur. [ citation needed ]


A nutritional anemia is a type of anemia that can be directly attributed to either a nutritional disorder or a nutritional deficiency.


A blood cancer or hematological malignancy is a type of malignant cancer that originates, affects, or involves the blood, bone marrow, or lymph nodes. [ 64 ]  These cancers include leukemias, lymphomas, and myelomas. These particular types of cancers can arise as defected mature cell types that have differentiated from hematopoietic precursor cells (often in the bone marrow) and begin to quickly proliferate through the bloodstream where it can then often infiltrate other organs and tissues. Others can involve the formation of tumors from  lymphoblasts  from within the lymphoid tissue. [ 65 ]  Incidence of affected people with a form of blood cancer has been steady increasing over recent years; however, due in part to early detection methods and subsequent advancements in the treatment of the diseases, mortality rates have continued to decrease. [ 66 ]


Leukemia is a malignancy producing of white blood cells in bone marrow. It can be a serious disease if not treated early.
Sometimes it can be cured by  chemotherapy  or  stem cell treatment . It can affect our bloodstream, skin, lymph nodes, heart, and brain.


is also related with  Blood Clot


Hematological disorders may be caused by a number of infection-related conditions involving the introduction of microorganisms into the host, such as  bacteria ,  viruses ,  microfilaria ,  fungus  and  protozoa . [ 40 ]


Hematologic diseases  are disorders which primarily affect the  blood  and  blood-forming organs . Hematologic diseases include rare genetic disorders,  anemia ,  HIV ,  sickle cell disease  and complications from chemotherapy or transfusions.


Hemochromatosis type 4  is a hereditary  iron overload  disorder that affects  ferroportin , an iron transport protein needed to export iron from cells into circulation. [ 1 ]   Although the disease is rare, it is found throughout the world and affects people from various ethnic groups.  While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage. [ 2 ]


Symptoms vary greatly between individuals with type 4 hemochromatosis.  This difference in symptoms is likely due to the different types of SLC40A1 mutations patients may have. [ 3 ]  In general, signs and symptoms of type 4 hemochromatosis are caused by excess iron in cells, which leads to tissue damage. The damage is largely due to iron-catalyzed oxidative reactions.  Iron can exchange electrons with a variety of substrates, which can lead to generation of reactive oxygen species.  This can lead to  oxidative stress ,  lipid peroxidation , and DNA damage, which may result in cell death. [ 4 ]   Two main forms of hemochromatosis type 4 exist (A and B), and the symptoms of these forms are distinct from one another. [ 3 ]


Type 4A hemochromatosis typically has milder symptoms than other types of hemochromatosis. Individuals with type 4A hemochromatosis tend to have hyperferritinemia (elevated ferritin in the blood plasma) and low saturated  transferrin  levels.  These individuals are likely to have liver and spleen iron overload, primarily in  Kupffer cells  and other macrophages. [ 5 ]   Because iron export is impaired, iron is unavailable for transport by circulating transferrin.  This iron unavailability potentially leads to mild anemia in type 4A hemochromatosis patients because iron is necessary for hemoglobin synthesis, and red blood cells have a relatively high turnover rate. [ 4 ]  Over time, iron stores increase, and individuals with type 4A hemochromatosis may develop hepatic fibrosis. [ 3 ]


The symptoms of type 4B hemochromatosis tend to be more severe. They resemble the symptoms of hemochromatosis types 1, 2, and 3. Plasma iron concentration is elevated, and symptoms include joint pain, diabetes, and arrhythmia. Liver iron deposition tends to be greater in type 4B than in type 4A. [ 5 ]   Liver damage occurs more frequently in this form of hemochromatosis than in type 4A, and some individuals develop cirrhosis of the liver. [ 3 ]


Type 4 hemochromatosis is caused by mutations of the SLC40A1 gene, located on the long arm of chromosome 2, specifically at 2q32.2.  The SLC40A1 gene encodes ferroportin, a protein responsible for exporting iron from cells in the intestine, liver, spleen, and kidney, as well as from reticuloendothelial macrophages and the placenta. [ 6 ] [ 7 ]  More than 39 mutations to the SLC40A1 gene have been identified in patients with type 4 hemochromatosis. [ 7 ]  All reported SLC40A1 mutations are deletions or missense mutations, which lead to amino acid substitution. [ 8 ]


Mutations to SLC40A1 that change the amino acid sequence can result in loss of function or gain of function for the resulting ferroportin protein. The loss of function mutation results in a phenotype that is different from that of a gain of function mutation, and these phenotypes are associated with two different forms of type 4 hemochromatosis.  Loss-of-function mutations are more frequent and are associated with type 4A hemochromatosis.  These mutations lead to a defect in the localization of ferroportin.  Gain-of-function mutations are associated with type 4B and lead to production of ferroportin that resists negative regulation by hepcidin. [ 8 ] [ 9 ]


Unlike other forms of hemochromatosis, which have a recessive pattern of inheritance, type 4 is an  autosomal dominant  dominant disorder. The dominant inheritance pattern occurs in hemochromatosis type 4 because ferroportin is multimeric. Consequently, mutant ferroportin can associate with wild-type ferroportin in multimers and interfere with the function of normal ferroportin proteins. [ 8 ]


In normal iron regulation, iron is absorbed in the intestine, and ferroportin transports iron from the cells of the intestinal lining into the bloodstream. Iron in the bloodstream is then bound by transferrin, which carries the iron to target cells. Iron is stored in cells and blood serum in a protein called  ferritin . Reticuloendothelial macrophages, which can phagocytose red blood cells, are important in the iron recycling process. Ferroportin is upregulated in the reticuloendothelial macrophages after phagocytosis occurs so that iron from the degraded red blood cells can be released into the bloodstream and transported to other types of cells as needed.   Hepcidin , a protein synthesized in the liver in response to iron or inflammation, is a regulator of ferroportin expression.  When hepcidin binds ferroportin, ferroportin is phosphorylated, endocytosed, tagged with ubiquitin, and degraded. [ 6 ] [ 7 ]  More than 39 mutations to the SLC40A1 gene have been identified in patients with type 4 hemochromatosis. [ 7 ]   The misregulation of ferroportin in type 4 hemochromatosis can involve a failure of ferroportin to be properly expressed at the cell membrane, or it can involve a failure of ferroportin to respond to negative regulation by hepcidin. [ 8 ]


Hemochromatosis type 4A is characterized by impaired iron export in cells. Reticuloendothelial macrophages are most affected.  Iron accumulates preferentially in Kupffer cells, which are located in the liver, and serum ferritin increases; less iron is available for circulating transferrin, a protein that binds iron and transports it through the bloodstream to cell receptors. [ 10 ] [ 11 ]   This means that, while iron is trapped in certain types of tissues, it cannot be transported to tissues where it is needed. The accumulation of iron in tissues due to impaired iron export can lead to increasing transferrin iron saturation and liver parenchymal iron overload in advanced stages of the disease. [ 3 ]  More ferritin is produced to suppress oxidative cell damage, although the amount of ferritin that cells can accumulate is limited. [ 12 ]


Hemochromatosis type 4B is characterized by abnormal iron release from macrophages and enterocytes because the mutant ferroportin is resistant to the hepcidin protein, which serves a regulatory function in wild-type ferroportin. [ 9 ]  Intestinal iron absorption and release of iron from macrophages is increased. [ 3 ]   Thus, this form of the disease leads to elevated transferrin saturation levels. [ 9 ]   Systemic iron overload results, and liver iron deposition is primarily in the hepatocytes. [ 13 ]


Diagnosis is based upon identification of symptoms, medical history, family history, and laboratory tests. Blood tests may show high levels of ferritin and low, normal, or high levels of transferrin saturation, depending on the form of hemochromatosis. The diagnosis must be confirmed by  genetic testing  for SLC40A1 mutations. [ 14 ]


Treatment is based on the symptoms and severity of the disease.  Iron chelators may be used to bind excess iron in tissues and allow for excretion of the excess metal. [ 15 ]   Individuals with hemochromatosis type 4B may be treated with therapeutic  phlebotomy . However, individuals with hemochromatosis type 4A may not require treatment. Additionally, therapeutic phlebotomy may not be tolerated in individuals with type 4A because anemia may develop despite the elevated serum ferritin levels typically found in these individuals. [ 11 ]


Ferroportin disease is rare. [ 16 ]


Hemoglobin C  (abbreviated as  HbC ) is an abnormal  hemoglobin  in which  glutamic acid  residue at the 6th position of the  β-globin  chain is replaced with a  lysine  residue due to a point mutation in the  HBB  gene. [ 1 ]  People with one copy of the gene for hemoglobin C do not experience symptoms, but can pass the abnormal gene on to their children. Those with two copies of the gene are said to have  hemoglobin C disease  and can experience mild  anemia . It is possible for a person to have both the gene for hemoglobin S (the form associated with  sickle cell anemia ) and the gene for hemoglobin C; this state is called  hemoglobin SC disease , and is generally more severe than hemoglobin C disease, but milder than sickle cell anemia. [ 2 ]


HbC was discovered by  Harvey Itano  and  James V. Neel  in 1950 in two African-American families. It has since been established that it is most common among people in West Africa. It confers survival benefits as individuals with HbC are  naturally resistant to malaria  caused by  Plasmodium falciparum ,  albeit incompletely.


People with one copy of the gene for hemoglobin C (termed  heterozygous ) do not experience significant symptoms, but can pass the abnormal gene onto their children; this condition is called hemoglobin C trait. When two hemoglobin C genes are present (termed  homozygous ), the individual is said to have hemoglobin C disease, and may develop mild  anemia , as red blood cells containing hemoglobin C have a decreased lifespan. The anemia in hemoglobin C disease is classified as  hemolytic , because it is caused by the destruction of red blood cells. An  enlarged spleen , and sometimes jaundice, may also occur. [ 1 ] [ 3 ] [ 4 ]  Some persons with this disease may develop  gallstones  that require treatment. [ 5 ]  Continued  hemolysis  may produce pigmented gallstones, an unusual type of gallstone composed of the dark-colored contents of red blood cells. [ 6 ]


The red blood cells of people with hemoglobin C disease are usually abnormally small ( microcytic ) with a high  mean corpuscular hemoglobin concentration  (MCHC). The high MCHC is caused by a decreased concentration of water inside the cells.  Target cells , microspherocytes, and HbC crystals can be seen on microscopic examination of  blood smears  from homozygous patients. [ 2 ]


HbC can combine with other abnormal hemoglobins and cause serious hemoglobinopathies. Individuals with sickle cell–hemoglobin C (HbSC), have inherited the gene for  sickle cell disease  (HbS) from one parent and the gene for hemoglobin C disease (HbC) from the other parent.  Since HbC does not polymerize as readily as HbS, there is less sickling in most cases. There are fewer acute vaso-occlusive events and therefore in some cases fewer sickle cell crises. The peripheral smear demonstrates mostly target cells, occasional hemoglobin C crystals, and only a few sickle cells.  However, persons with hemoglobin SC disease (HbSC) have more significant retinopathy, ischemic necrosis of bone, and priapism than those with pure SS disease. [ 2 ]


There are also a few cases of HbC in combination with  HbO ,  HbD  and  beta thalassemia . [ 1 ]


Hemoglobin C is produced when a point mutation in the  HBB  gene causes amino acid substitution of glutamic acid to lysine at the 6th position of the  β-globin  chain of the hemoglobin. The mutation can be homozygous, occurring on both the chromosomes (alleles), or heterozygous, affecting only one allele. [ 1 ]  Under heterozygous condition, people are said to have hemoglobin C  trait , or as hemoglobin C carriers, and they have one gene for HbC with either one HbA gene or HbS gene. Their red blood cells contain both hemoglobin C and either normal  hemoglobin A  or hemoglobin S. Hemoglobin C mutation is an autosomal recessive disorder that results from the biparental inheritance of the allele that encodes for hemoglobin C. [ 6 ]  If both parents are carriers of hemoglobin C, there is a chance of having a child with hemoglobin C disease. Assuming both parents are carriers, there is a 25% chance of having a child with hemoglobin C disease, a 50% chance of having a child who is a carrier of hemoglobin C, and a 25% chance of having a child who is neither a carrier nor affected by hemoglobin C disease. [ 4 ]


This mutated form reduces the normal plasticity of host  erythrocytes  causing a  hemoglobinopathy . In those who are  heterozygous  for the mutation, about 28–44% of total hemoglobin (Hb) is HbC, and no  anemia  develops. In  homozygotes , nearly all Hb is in the HbC form, resulting in mild  hemolytic anemia , jaundice and enlargement of spleen. [ 1 ]


Individuals with HbC have reduced risk of  P. falciparum  malaria infection. [ 7 ]  HbC has been described as being more advantageous than HbS because, even in homozygous individuals, it is usually non-fatal. [ 8 ]  However, in contrast to HbS, it does not prevent malaria due to  P. vivax, [ 9 ]  and is less effective in resistance to falciparum malaria in heterozygous conditions. [ 7 ]  Homozygous HbC is more resistant to heterozygous condition, or to thalassemias. [ 10 ] [ 11 ]  But HbC mutation  does not prevent the infection.  P. falciparum  do not survive in red blood cells with homozygous hemoglobins, but can survive in the presence of heterozygous hemoglobins. [ 10 ]  HbC reduced the binding force (cytoadherence) of  P. falciparum  by reducing the activity of  PfEMP1 . [ 12 ]  Evidences indicate that HbC reduced the level of  PfEMP1, which is required for effective binding and invasion of RBC by the malarial parasite. [ 13 ]  It has been predicted that with the trend of HbC mutation and falciparum prevalence, HbC would replace HbS in central West Africa in the future. [ 10 ]


Physical examination may show an enlarged spleen. Tests that may be done include:  complete blood count  (CBC),  hemoglobin electrophoresis , and  peripheral blood smear . [ 5 ]


Genetic counseling may be appropriate for high-risk couples who wish to have a baby. [ 14 ]


Usually no treatment is needed.  Folic acid  supplementation may help produce normal red blood cells and improve the symptoms of anemia  [ 14 ]


Overall, hemoglobin C disease is one of the more  benign   hemoglobinopathies . [ 6 ]  Mild-to-moderate reduction in RBC lifespan may accompany from mild hemolytic anemia.  Individuals with hemoglobin C disease have sporadic episodes of musculoskeletal (joint) pain. [ 6 ]  People with hemoglobin C disease can expect to lead a normal life. [ 14 ]


Hemoglobin C is found most abundantly in areas of West Africa, such as Nigeria, where  Yorubas  live. [ 15 ] [ 16 ] [ 17 ]  Hemoglobin C gene is found in 2-3% of  African-Americans [ 4 ]  while 8% of African-Americans have hemoglobin S (Sickle) gene. Thus Hemoglobin SC disease is significantly more common than Hemoglobin CC disease. The trait also affects people whose ancestors came from  Italy ,  Greece ,  Latin America , and the  Caribbean  region. [ 4 ]  However, it is possible for a person of any race or nationality to have hemoglobin C trait. In terms of geographic distribution, the hemoglobin C allele is found at the highest frequencies in  West Africa , where it has been associated with protection against  malaria . [ 3 ]  Hemoglobin C disease is present at birth, though some cases may not be diagnosed until adulthood. Both males and females are affected equally. [ 6 ]


Studying the molecular basis of  sickle cell disease ,  Linus Pauling  and  Harvey Itano  at the California Institute of Technology discovered in 1949 that the disease was due to abnormal hemoglobin called HBS. [ 18 ] [ 19 ]  In 1950, Itano and  James V. Neel  discovered from two African-American families a different blood condition very similar to sickle cell disease. [ 20 ] [ 21 ]  Five of the ten individuals indicated sickled RBCs. But the condition was harmless as the individuals had no anaemia. Thus, it was not clear whether it was involved in sickle cell disease. Genetically, the abnormal hemoglobin was only in  heterozygous  condition. [ 22 ]  The next year, Neel and his colleagues established that the hemoglobin is associated with sickle cell disease. [ 23 ]


The hemoglobin was named hemoglobin III, [ 24 ]  but hemoglobin C was eventually used. [ 25 ] [ 26 ]  By 1954, it was found that the mutant hemoglobin was highly prevalent in West Africa. [ 27 ] [ 28 ]  In 1960,  Vernon Ingram  and J. A. Hunt at the University of Cambridge discovered that the mutation was a single amino acid replacement of glutamic acid with lysine. [ 29 ]


Hemoglobin D  ( HbD ) is a  variant of hemoglobin , a protein complex that makes up  red blood cells . Based on the locations of the original identification, it has been known by several names such as  hemoglobin D-Los Angeles ,  hemoglobin D-Punjab , [ 1 ]   D-North Carolina ,  D-Portugal ,  D-Oak Ridge , and  D-Chicago. [ 2 ]  Hemoglobin D-Los Angeles was the first type identified by  Harvey Itano  in 1951, and was subsequently discovered that hemoglobin D-Punjab is the most abundant type that is common in the  Sikhs  of Punjab (of both Pakistan and India) and of Gujarat. [ 3 ]


Unlike normal adult human hemoglobin ( HbA ) which has  glutamic acid  at its 121 amino acid position, it has  glutamine  instead. [ 4 ]  The single amino acid substitution can cause various  blood diseases , from fatal genetic anemia to mild  hemolytic anemia , an abnormal destruction of red blood cells. [ 5 ]  Depending on the type of genetic inheritance, it can produce four different conditions: [ 4 ]  heterozygous (inherited in only one of the chromosome 11) HbD trait, HbD- thalassemia , HbS-D ( sickle cell ) disease, and, very rarely, homozygous (inherited in both chromosome 11) HbD disease. [ 6 ]  It is the fourth hemoglobin type discovered after HbA, HbC and HbS; [ 1 ]  the third hemoglobin variant identified after HbC and HbS; [ 2 ]  and the fourth most common hemoglobin variant after HbC, HbS, and HbO. [ 5 ]


Hemoglobin was discovered as some sort of crystal formed from earthworm body fluid and animal blood by German biochemist Friedrich Ludwig Hünefeld at  Leipzig University  in 1840. [ 7 ] [ 8 ]  When the protein nature was established another German  Felix Hoppe-Seyler  gave the name hemoglobin (literally "blood protein") in 1864. [ 9 ] [ 10 ]  Its role as an oxygen transporter was later established. [ 1 ]  While studying  sickle cell disease ,  Linus Pauling  and  Harvey Itano  at the  California Institute of Technology  discovered in 1949 that the disease was due to abnormal hemoglobin, later called hemoglobin S (HbS). [ 11 ] [ 12 ]  In 1950, Itano and  James V. Neel  discovered a slightly different case in which individuals had sickled red blood cells but not anemia. [ 13 ] [ 14 ]  The hemoglobin was named hemoglobin III, [ 15 ]  but later known as hemoglobin C (HbC). [ 16 ] [ 17 ]


In 1934, Jean V. Cooke and J. Keller Mack, pediatricians at St. Louis, USA, reported a case of white American family which had some member suffering from sickle cell anemia. [ 18 ] [ 19 ]  Of six siblings, two children had anemia, while others, including their parents, were healthy. Blood tests indicated the two children had sickled red blood cells, but with uncharacteristically slow process of sickling. The father, who had no disease, was found to have sickled re blood cells. [ 18 ]  With the new techniques for identifying different hemoglobin, Itano investigated the family and found that like their father, three other children had abnormal hemoglobin but without the disease or sickled cells; their hemoglobin giving same mobility (in  electrophoresis ) and but different solubility as sickled cells. He recorded in 1951:


The resent report deals with the identification of still another form of human hemoglobin in five members of a family in which the genetic picture is not typical of sickle cell anemia, although two of the members have in the past been diagnosed as having sickle cell anemia. An earlier study of this family disclosed that the two anemic children and the father, who was not anemic, had sickling erythrocytes while the mother, two sisters and two brothers of the anemic children had non-sickling erythrocytes and were not anemic. [ 20 ]


In the paper published in the  Proceedings of the National Academy of Sciences of the United States of America , Itano presented the need to have naming convention for the different types of hemoglobin, and introduced the alphabet-coding system such as hemoglobin  a  (for normal adult type),  b  (sickle cell type),  c  (sickle cell-associated type) and  d  (for the novel type); as he explained:


In order to facilitate the discussion in the present paper and to avoid confusion in future works, it seems desirable at this time to establish a system of symbols for identifying the various forms of adult human hemoglobin... normal hemoglobin, sickle cell hemoglobin, the abnormal hemoglobin reported by Itano and Neel, and the abnormal hemoglobin reported in the present paper will be designated adult human hemoglobins a, b, c and d, respectively, more briefly as hemoglobins a, b, c and d. [ 20 ]


It was the discovery of hemoglobin D and creation of hemoglobin naming system. [ 3 ]  In 1953, Amoz Immanuel Chernoff at the Washington University School of Medicine, St. Louis, introduced the capitalised-letter designation such as A (for normal adult type), C (second abnormal type), D (third abnormal type), S (sickle cell type) and F (fetal form). [ 21 ]  Although the nomeclature system became a convention, hemoglobin D, in particular, became known by various names, generally based on their origin of identification; like hemoglobin D-Los Angeles for the first discovered, [ 19 ]  hemoglobin D-Punjab, [ 1 ]  D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago. [ 2 ]  By 1961, it was known that the structural difference of HbD from HbA was in the β-chain. [ 22 ]  Around the same time, Corrado Baglioni of Massachusetts Institute of Technology identified the exact abnormality that substitution of glutamic acid with glutamine at position 121 in the β-chain was the basis of HbD, the findings which he reported in 1962. [ 23 ]


Hemoglobin D has the basic structure and composition of normal adult hemoglobin. It is a globular protein containing  prosthetic  (non-protein) group called heme. There are four individual peptide chains, namely two α- and two β-subunits, each made of 141 and 146 amino acid residues, respectively. One heme is associated with each chain and responsible for binding free oxygen in the blood. A single HbD is therefore a  tetramer  (containing four molecules), denoted as α 2 β 2 . [ 24 ]  Each subunit has a molecular weight of about 16,000 Da ( daltons ), making the tetramer about 64,000 Da (64,458 g/mol) in size. [ 25 ]  HbD is different from HbA only on the β-subunit where the amino acid glutamic acid at 121 position is replaced with glutamine (α 2 β 2 121Glu→Gln ). [ 4 ]  It has the same chemical characteristic as HbS (a hemoglobin of sickle cell trait), with one fewer negative charge at an alkaline pH than HbA. However, unlike HbS, it does not produce sickled RBC on its own under low level of oxygen. [ 4 ]


Hemoglobin D is synthesised due to mutation in  HBB , the gene that produces β-subunits of hemoglobin and is present on human chromosome 11. A point mutation in the first base of the 121 codon that normally has GAA sequence for normal hemoglobin is changed to CAA. [ 26 ] [ 27 ]  GAA codes for glutamic acid, while CAA for glutamine. [ 28 ]  This gene mutation makes HbD, which can further give rise to several genetic and disease conditions. The specific mutations can occur at different sites of the gene. According to the Globin Gene Server database, there are other types of HbD such as HbD-Agri ( HBB :c.29C→A;364G→C), HbD-Bushman ( HBB :c.49G→C), HbD-Ouled Rabah ( HBB :c.60C→A or 60C→G), HbD-Iran ( HBB :c.67G→C), HbD-Granada ( HBB :c.68A→T), HbD-Ibadan ( HBB :c.263C→A) and HbD-Neath ( HBB :c.365A→C). [ 1 ]


Depending on the nature of inheritance of HbD mutation there are four conditions, some of which can be deadly diseases: [ 6 ]


Hemoglobin in combination with normal hemoglobin (heterozygous HBD/HbA) is asymptomatic, causing no effects. Individuals have normal hemoglobin level and their red blood cells are normal spherical structure. [ 29 ]  Homozygous HbD/HbD causes mild hemolytic anemia and chronic non-progressive  splenomegaly  (enlargement of  spleen ). [ 4 ]  Heterozygous HbD/HbS causes sickle cell anemia. However, most cases of the disease are milder than the usual HbS/HbS conditions. The most serious complication noted is stroke. HbD-thalassemia causes microcytic anemia which is generally milder that in typical thalassemia. [ 29 ]


As hemoglobin can be inherited in several conditions, no single diagnostic test can confirm the specific protein completely. Electrophoresis is one of the most commonly used and requires sequential identification with other hemoglobins. All hemoglobins can be separated in cellulose acetate at pH 8.6 and in agarose gel at pH 6.2. In alkaline medium of cellulose acetate, HbD moves slower and can be identified at shorter distance than HbA, but it migrates exactly as HbS. It can be differentiated from HbS in acidic agarose gel in which it moves faster and farther than HbS, but at the same level with HbA. [ 30 ] [ 31 ]   High-performance liquid chromatography  (HPLC) can directly detect the protein, but its specific identification of HbD from other hemoglobins can be inconclusive. [ 32 ]  HPLC coupled with  mass spectrometry  (HPLC-ESI-MS/MS) can accurately detect the protein but the procedure is costly and time consuming. [ 33 ]  Genetic screening can be done with  polymerase chain reaction  that can identify HbS from other hemoglobin variants. [ 34 ]


Hemoglobin D conditions such as homozygous and HbD/HbA heterozygous do not require medical intervention. HbD/HbS and HbD-thalassemia conditions are managed like the typical cases of sickle cell anemia and thalassemia. [ 29 ]  In case of sickle cell anemia, daily treatment with  penicillin  recommended up to five years of age. [ 35 ]  Dietary supplementation of  folic acid  is recommended by the  WHO . [ 36 ]  In 2019,  Crizanlizumab , a monoclonal antibody was approved by the United States FDA for reducing the frequency of blood vessel blockage in 16 years and older individuals. [ 37 ]  For thalassemia, regular lifelong  blood transfusions  is the usual treatment.  Bone marrow transplants  can be curative for some children. [ 38 ]  Medications like  deferoxamine ,  deferiprone  and  luspatercept . [ 39 ]   Gene therapy ,  exagamglogene autotemcel  is approved for medical use in the United Kingdom since November 2023. [ 40 ] [ 41 ]


Hemoglobin D is most abundant among Sikhs, with occurrence of 2% in Punjab and 1% in Gujarat. It is also found in small number of individuals among Africans, Americans and Europeans who usually had close ethnicity with Indians in the past. [ 5 ]  It is below 2% among the African-Americans. [ 4 ]  Combination with β-thalassemia and HbS are known in south and east India; the first resulting in thalassemia and the latter in sickle cell anemia. [ 5 ]


There is also high occurrence in China, with prevalence rate of 12.5% in  Chongqing . [ 42 ]  It is sporadically recorded in some Turkish, Algerian, West African, Saudi Arabian, native American, English, and Irish population. [ 29 ]  Rare conditions like HbD/HbJ, [ 43 ]  HbD/ HbQ, [ 44 ]  and HbD/Hb Fontainebleau [ 45 ]  are also found in India. A rare case of HbS/HbD is reported from Pakistan in which individuals are diagnosed with bone infection ( osteomyelitis ). [ 31 ]  An isolated condition of HbD/HbC is recorded in US. [ 46 ]


Hemoglobin H disease , also called  alpha-thalassemia intermedia , is a disease affecting  hemoglobin , the oxygen carrying molecule within  red blood cells . It is a form of  Alpha-thalassemia  which most commonly occurs due to  deletion  of 3 out of 4 of the  α-globin  genes. [ 1 ]


Hemoglobin H disease is a genetic disorder resulting in absent or impaired production of the  α-globin  protein, a normal component of the hemoglobin. The disease occurs when the α-globin  gene expression  is reduced to less than 30% of the normal expression. [ 2 ]  In a healthy individual there are four copies of the gene which encode the alpha-globin protein.  Alpha-globin  is encoded by the  HBA1  (2 copies) and  HBA2  (2 copies) genes. The  genotype  of healthy individuals with four normal copies of α-globin is annotated as αα/αα. In individuals with deletional Hb H disease, there is deletion of three of the four  α-globin  alleles, which is annotated as --/-α. [ 3 ]  Non-deletional Hb H disease refers to a decreased alpha-globin that has not occurred as a result of the complete deletion of the  DNA sequences  encoding HBA1 and HBA2, and this is more rare than the deletional type. [ 4 ]


The most common hemoglobin found within adult  red blood cells  is  Hemoglobin A . The structure of Hb A consists of two  α-globin  chains bound to two  β-globin  chains to form a  tetramer  (a protein made up four protein chains). [ 3 ]  When there is lower than normal production of  α-globin , as in Hb H disease, the excess  β-globin  form β 4 -tetramers, termed Hemoglobin H. These β 4 -tetramers accumulate in red blood cells and precipitate to form Hb H  inclusion bodies . The inclusion bodies in the mature red blood cells are removed by the  spleen  and this results in an early destruction of these red blood cells. This destruction of red blood cells by the spleen is termed  extravascular hemolysis . [ 4 ]   Hemoglobin F  is the predominant form in the  fetus  and it also contains  α-globin , thus, in severe cases the disease can affect  fetal development . [ 3 ]


The prevalence of Hemoglobin H disease mirrors that of the  hemoglobinopathies .  As a whole, they are most prevalent in individuals of Asian, African, and Mediterranean decent. [ 5 ]  There is a protective effect against malaria for individuals carrying thalassemia genes, which explains the high frequency of thalassemia within the worldwide population. [ 3 ]


Patients with Hemoglobin H Disease present with chronic  hemolytic anemia  that ranges in severity form mild to moderate disease.  Anemia  is the most common presenting symptom of patients with Hb H disease . Other common clinical features include jaundice, splenomegaly, hepatomegaly, and gallstones. All of these symptoms are related to the destruction of the red blood cells in the spleen and the associated increased  hemoglobin metabolism . Patients with non-deletional Hb H disease are more likely to be symptomatic and have severe disease presentation when compared to individuals with deletional Hb H disease. Disease presentation varies from asymptomatic individuals to  neonatal  growth retardation and death in the most severe cases. Death in the neonatal period occurs due to the severe anemia resulting in  Hydrops Fetalis . [ 4 ]


Patients most often present initially due to hemolytic episodes that occur during times of  infection  or  inflammation . During these episodes, patients may develop hemolytic crisis, in which there is a rapid drop in the hemoglobin due to increased red blood cell destruction. [ 4 ]


Hemoglobin analysis, with tests such as  high-performance liquid chromatography , along with  genetic testing  are required for the confirmation of Hb H disease. [ 6 ] [ 7 ]  Patients may also laboratory abnormalities indicative of low red blood cells, including changes in hemoglobin,  red cell distribution width ,  hematocrit ,  mean corpuscular hemoglobin , and  mean corpuscular volume . [ 4 ]  A  peripheral blood smear  stained with  brilliant cresyl blue  will show inclusion bodies within the red blood cells. [ 7 ] [ 4 ]


Due to the fact that Hb H disease does not commonly present with severe anemia, all patients do not require treatment or intervention. Some patients may require  folic acid  supplementation due to the increased turnover of red blood cells. In cases of hemolytic crisis, patients are treated with a  blood transfusion  and treatment of the underlying cause. In severe cases, regular blood transfuions may be needed, and these patients should be monitored for development of  iron overload . For these severe cases,  stem cell transplantation  can be curative. [ 4 ]


Hemoglobin J  is an abnormal  hemoglobin , an  alpha globin  gene variant and present in various geographic locations. It was first reported in a black American family [ 1 ]  in 1956, and later reported from Indonesia, India, and other parts of the world. Hemoglobin J reported from Meerut India shows the  mutation  of 120th  alanine  to  glutamic acid  on  alpha chain . [ 2 ]  Hemoglobin J was also reported from  Chhattisgarh , Central India as revealed by Lingojwar and coworkers in 2016. [ citation needed ]


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


Hemoglobin O  ( HbO ) is a rare type of  hemoglobin  in which there is a substitution of  glutamic acid  by  lysine  as in  hemoglobin C , but at different positions. Since the amino acid substitution can occur at different positions of the  β-globin chain  of the protein, there are several variants. In  hemoglobin O-Arab  (HbO-Arab) substitution occurs at position 121, [ 1 ]  while in hemoglobin O-Padova (HbO-Padova) it is at 11 position, [ 2 ]  and in hemoglobin O Indonesia (HbO Ina ) it is at 116. [ 3 ]


HbO is usually harmless unlike other hemoglobin variants such as  HbS  and  thalassemias , even under combination with these abnormal hemoglobins. Hemoglobin O-Padova is the most severe form and is associated with disease of the RBCs and spleen.


Hemoglobin O Indonesia is the first discovered HbO. Lie-Injo Luan Eng at the  University of Indonesia , Djakarta, was the first to notice the abnormal hemoglobin in 1956 among the  Buginese people  of Sulawesi Island in Indonesia. It was found among normal hemoblobin ( HbA ) of the blood samples but different under  electrophoresis . It also showed different characters form HbS and HbC, and did not cause  sickling of RBCs . The discovery went unnoticed as he later remarked, "This report, however, did not attract any attention as it was written in the Indonesian language." [ 4 ]  He again reported his observation in  The Lancet  the next year. [ 3 ]  After consulting  Hermann Lehmann  at the  St Bartholomew's Hospital  in London and T.H.J. Huisman at the  State University of Groningen  in the Netherlands, and letting experimentally verified by  Harvey Itano  at the  California Institute of Technology , he was convinced that his discovery was a new type of hemoglobin. He gave the name "hemoglobin Buginese X" as he reported in  The British Medical Journal  in 1958, concluding:


As it has been confirmed by different laboratories that Buginese X differs from all other known haemoglobins, it should be allotted a letter. N was the letter most recently used to designate haemoglobin Liberian I (personal communication by Dr.  James V. Neel ). So far as we know, the letter 0 has not yet been used, and therefore Buginese X should be called Hb 0. Dr. James V. Neel agreed with this choice. [ 4 ]


The same hemoglobin type was found in Iran in 1973. It was found that the protein modification was at position 116 where lysine was present in place of glutamic acid. [ 5 ]  In 1978, a similar case was reported from Italy. [ 6 ]  The hemoglobin was eventually named hemoglobin O Indonesia. [ 7 ]


In 1960, a different but related hemoglobin was found from an 8-year-old Arab boy at  Jisr az-Zarqa  in Israel. [ 8 ] [ 9 ]  As the boy had severe pneumonia and blood abnormality ( hemoglobinopathy ) including sickled RBCs. His Hemoglobin was different from HbC and HbS and was designated as hemoglobin O (HbO). On investigating his family, his father was found to be the HbO carrier (i.e.  heterozygous  HbA/HbO) while her mother HbS carrier. Out of the six siblings, three had no HbO (though one has HbS), one had a heterozygous HbO. The boy and his older sister were diagnosed with sickle cell disease due to inherited HbS/HbO combination. [ 8 ]  It was later found that the amino acid replacement is at position 121 of the hemoglobin. The hemoglobin is now known as hemoglobin O-Arab. [ 1 ]


In 1974, another abnormal hemoglobin which they called hemoglobin O-Padova was identified from an Italian woman in Padova. [ 10 ]  It showed glutamic acid to lysine substitution at position 11. [ 11 ]  The woman was suffering from a complicated blood conditions. The mother and one of the two children indicated the same hemoglobin but without any symptom. [ 10 ]


Hemoglobin O Indonesia is mostly harmless. But some individuals may indicate mild anemia. [ 4 ]  Even under heterozygous condition such as with HbD, no serious symptom is observed. [ 12 ]  With HbS, there can be mild  sickle cell trait  but no symptoms. [ 13 ] [ 14 ]


Hemoglobin O-Arab causes sickle cell disease in heterozygous (HbS/HbO) individuals. However, the symptomatic anemia is mild and is not life-threatening. It is even milder than in heterozygous sickle cell trait (HbS/HbA). [ 15 ]  A case of  sickle cell retinopathy  is documented. [ 16 ]  Under  homozygous  condition, it is also linked with  jaundice  (conjugated hyperbilirubinemia), [ 9 ]  and mild anemia. [ 17 ]


Hemoglobin O-Padova in homozygous condition is associated with complex genetic and physiological anomalies. In the first woman diagnosed, severe RBC damage ( dyserythropoietic anemia ), enlargement of spleen ( splenomegaly ), and abnormal RBC (hereditary erythroblastic multinuclearity). [ 10 ]  But heterozygous condition is clinically harmless. [ 10 ]


Hemoglobinopathy  is the medical term for a group of inherited  blood disorders  involving the  hemoglobin , the protein of  red blood cells . [ 1 ]  They are generally  single-gene disorders  and, in most cases, they are inherited as  autosomal   recessive  traits. [ 2 ] [ 3 ]


There are two main groups: abnormal structural hemoglobin variants caused by mutations in the hemoglobin genes, and the  thalassemias , which are caused by an underproduction of otherwise normal hemoglobin molecules. The main structural hemoglobin variants are HbS, HbE and HbC. The main types of thalassemia are  alpha-thalassemia  and  beta thalassemia . [ 4 ] [ 2 ]


Hemoglobin is a  protein  containing  iron  that facilitates the transportation of  oxygen  in  red blood cells . [ 5 ]  Hemoglobin in the  blood  carries oxygen from the  lungs  to the other tissues of the body, where it releases the oxygen to enable  aerobic respiration  which powers the  metabolism . Normal levels of hemoglobin vary according to sex and age in the range 9.5 to 17.2 grams of hemoglobin in every deciliter of blood. [ 6 ]


Hemoglobin also transports other gases. It carries off some of the body's respiratory  carbon dioxide  (about 20–25% of the total) [ 7 ]  as  carbaminohemoglobin , in which CO 2  binds to the  heme protein . The molecule also carries the important regulatory molecule  nitric oxide  bound to a  thiol  group in the globin protein, releasing it at the same time as oxygen. [ 8 ]


Normal human hemoglobins are  tetrameric proteins  composed of two pairs of globin chains, each of which contains one α (alpha) chain and one β (beta) chain. Each globin chain is associated with an iron-containing  heme   moiety . Throughout life, the synthesis of the α and the β chains is balanced so that their ratio is relatively constant and there is no excess of either type. [ 9 ]


The specific α and β chains that are incorporated into Hb are highly regulated during development: [ 10 ]


Hemoglobin structural variants manifest a change in the structure of the Hb molecule. The majority of hemoglobin variants do not cause disease and are most commonly discovered either incidentally or through newborn screening. Hb variants can usually be detected by protein-based  assay  methods such as  electrophoresis , [ 15 ]   isoelectric focusing , [ 16 ]  or  high-performance liquid chromatography . [ 17 ]  Diagnosis is commonly confirmed by  DNA sequencing . [ 18 ]


The hemoglobin structural variants can be broadly classified as follows: [ 19 ]


Methemoglobinemia  is a condition caused by elevated levels of  methemoglobin  in the blood. Methaemoglobin is a form of hemoglobin that contains the  ferric  [Fe 3+ ] form of iron, instead of the  ferrous  [Fe 2+ ] form . Methemoglobin cannot bind  oxygen , which means it cannot carry oxygen to tissues. In human  blood  a trace amount of methemoglobin is normally produced spontaneously; the enzyme  methemoglobin reductase  is responsible for converting methemoglobin back to  hemoglobin . [ 23 ] [ 24 ]  Methemoglobinemia can be hereditary but more commonly occurs as a side effect of certain medications or by abuse of  recreational drugs . [ 25 ]


Thalassemias  are quantitative defects that lead to reduced levels of one type of globin chain, creating an imbalance in the ratio of alpha-like chains to beta-like chains. This ratio is normally tightly regulated to prevent excess globin chains of one type from accumulating. The excess chains that fail to incorporate into normal hemoglobin can form non-functional aggregates that precipitate. This can lead to premature RBC destruction in the bone marrow and/or in the peripheral blood. Thalassemia subtypes of clinical significance are  alpha thalassemia  and  beta thalassemia . A third subtype,  delta thalassemia , affects production of HBA2 and is generally asymptomatic. [ 26 ]


The severity of alpha thalassemia depends on how many of the four genes that code for  alpha globin  are faulty. In the fetus, a deficiency of alpha globin results in the production of  Hemoglobin Barts  - a dysfunctional  hemoglobin  that consists of four  gamma globins . In this situation, a fetus will develop  hydrops fetalis  and normally die before or shortly after birth. [ 27 ]  In adults alpha thalassemia manifests as  HbH disease . In this, excess  beta-globin  forms β 4 -tetramers, which accumulate and precipitate in red blood cells, damaging their membranes. Damaged RBCs are removed by the  spleen  resulting in moderate to severe anemia. [ 28 ]


In beta thalassemia, reduced production of beta globin, combined with a normal synthesis of alpha globin, results in an accumulation of excess unmatched alpha globin. This precipitates in the red cell precursors in the bone marrow, triggering their premature destruction. Anemia in beta thalassemia results from a combination of ineffective production of RBCs, peripheral  hemolysis , and an overall reduction in hemoglobin synthesis. [ 29 ]


A combination hemoglobinopathy occurs when someone inherits two different abnormal hemoglobin genes. If these are different versions of the same gene, one having been inherited from each parent it is an example of  compound heterozygosity .


Both alpha- and beta- thalassemia can coexist with other hemoglobinopathies. Combinations involving alpha thalassemia are generally benign. [ 30 ] [ 31 ]


Some examples of clinically significant combinations involving beta thalassemia include:


There are two clinically significant combinations involving the sickle cell gene:


Hemoglobin variants are not necessarily pathological. For example, Hb Lepore-Boston and G-Waimanalo are two variants which are non-pathological. [ 38 ]  There are in excess of 1,000 known hemoglobin variants. [ 39 ]  A research database of hemoglobin variants is maintained by  Penn State University . [ 40 ]  A few of these variants are listed below.


Some hemoglobinopathies seem to have given an evolutionary benefit, especially to  heterozygotes , in areas where  malaria  is endemic. Malaria parasites infect red blood cells, but subtly disturb normal cellular function and subvert the immune response. A number of mechanisms have been propsed to explain the increased chance of survival for the carrier of an abnormal hemoglobin trait. [ 41 ]


Hemolytic jaundice , also known as prehepatic jaundice, is a type of  jaundice  arising from  hemolysis  or excessive destruction of red blood cells, when the byproduct  bilirubin  is not excreted by the  hepatic  cells quickly enough. [ 1 ]  Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the  liver  does not contribute to this type of jaundice. [ 1 ]


As one of the three categories of  jaundice , the most obvious sign of hemolytic jaundice is the discolouration or yellowing of the  sclera  and the  skin  of the patient, but additional symptoms may be observed depending on the underlying causes of  hemolysis . Hemolytic causes associated with bilirubin overproduction are diverse and include disorders such as  sickle cell anemia , [ 2 ]   hereditary spherocytosis , [ 3 ]   thrombotic thrombocytopenic purpura , [ 4 ]   autoimmune hemolytic anemia , [ 5 ]  hemolysis secondary to drug toxicity, [ 6 ]   thalassemia minor , [ 7 ]  and  congenital dyserythropoietic anemias . [ 8 ]   Pathophysiology  of hemolytic jaundice directly involves the  metabolism  of  bilirubin , where overproduction of  bilirubin  due to  hemolysis  exceeds the liver's ability to  conjugate  bilirubin to  glucuronic acid . [ 9 ]


Diagnosis  of hemolytic jaundice is based mainly on visual assessment of the yellowing of the patient's  skin  and  sclera , while the cause of  hemolysis  must be determined using laboratory tests. [ 10 ]  Treatment of the condition is specific to the cause of  hemolysis , but intense  phototherapy  and  exchange transfusion  can be used to help the patient excrete accumulated  bilirubin . [ 11 ]  Complications related to hemolytic jaundice include  hyperbilirubinemia  and  chronic bilirubin encephalopathy , which may be deadly without proper treatment. [ 12 ] [ 13 ]


The signs and symptoms additional to the development of a yellowish colour in the  sclera  and  skin  are specific to the causes of  hemolysis .


For example, if the patient has hemolytic  jaundice  resulting from  sickle cell disease , vaso-occlusive phenomena like acute vaso-occlusive pain and  acute chest syndrome  may be observed in the acute phases, while in  anemia , neurologic deficits and various  pulmonary  conditions may manifest in the  chronic  phase. [ 2 ]


Regardless of the causes, laboratory-confirmed elevation is predominantly seen in unconjugated  bilirubin . [ 10 ]  Serum  bilirubin  concentration rarely exceeds 4 mg/dL, unless the patient has concurrent liver disease. [ 14 ]


The underlying causes of hemolytic jaundice, as its name suggests, are disorders associated with  hemolysis . Such disorders are manifold and the common causes include:


Other less commonly observed causes of hemolysis include:


The above list is not exhaustive, and rare causes of  hemolysis  such as  Bartonella infection , [ 18 ]   hemolysis  due to  transfusion reactions , [ 19 ]  and  microangiopathic hemolytic anemia [ 20 ]  should be suspected when symptoms specific to those causes manifest.


The mechanisms by which  bilirubin  is overproduced in hemolytic jaundice can be understood in relation to the two major sites of  hemolysis : intravascular and extravascular.


During  intravascular hemolysis , red blood cells are broken down within the  vasculature , allowing  hemoglobin  from the ruptured  red blood cells  to form haptoglobin-hemoglobin complexes with  haptoglobin , which will be internalized and degraded by  hepatocytes  and the  spleen . [ 21 ]  If the degree of  hemolysis  is abnormally high, the unbound  hemoglobin  is converted to  methemoglobin  from which the  heme  moiety is bound to  hemopexin  or to  albumin , and both heme-hemopexin and heme-bound albumin are internalized by hepatocytes and subsequently degraded to  bilirubin . [ 22 ] [ 10 ]


During  extravascular hemolysis ,  red blood cells  are destroyed by  phagocytosis  by  macrophages  in the  reticuloendothelial system  and digested by  phagosomes . [ 23 ]  Hemoglobin within red blood cells are then degraded to release  heme , which will be converted by  microsomal heme oxygenase  to  iron ,  carbon monoxide  and  biliverdin , and are immediately reduced to unconjugated  bilirubin  by  biliverdin reductase  and released into the plasma. [ 24 ]


In both settings of  hemolysis  mentioned above, only low levels of conjugated  bilirubin  may accumulate in the serum, with the amount falling within the normal limits of 4 percent of total bilirubin as conjugated bilirubin can be efficiently excreted in bile through being secreted across canalicular membrane. [ 25 ]  Increased levels of conjugated bilirubin will only be observed with coexisting hepatobiliary abnormalities. Only when the canalicular excretion capacity is exceeded, conjugated bilirubin will accumulate in the plasma. [ 26 ]  As unconjugated bilirubin has a high affinity to albumin, at high level it is not efficiently cleared through  glomerular filtration  and it binds to the  elastic tissue  of the  skin  and  sclera , where high  albumin  content can be found. [ 25 ]  This explains the yellow discolouration observed in these tissues in hemolytic jaundice.


Symptoms  of  jaundice  can be observed superficially, thus visual methods are used to identify the condition. [ 27 ]  However, underlying causes of  jaundice  must be diagnosed through laboratory testing. [ 28 ]


In both newborns and adults, yellowing of the skin is a marker for jaundice. [ 27 ]  As most cases of  jaundice  are observed in newborns, healthcare workers use visual methods to identify the presence of this condition. [ 29 ]  A clinical  jaundice  scale, an adapted version of the Kramer's scale, is used to quantify the severity of jaundice through the spread of skin discoloration from zone 1, the head, to zone 5, the palms and soles of the neonate's body. [ 29 ] [ 30 ]  Cephalocaudal progression of jaundice to zone 4 and 5 of the Kramer's scale shows a significant positive correlation with serum  bilirubin  concentration of at least 11.0 mg per 100 ml, indicating the need for treatment. [ 29 ]


Conjunctival icterus  can be quantified by the Jaundice Eye Colour Index (JECI) through digital photography of the  sclera , where a JECI of 0 indicates a white colour, and a JECI of 0.1 indicates an intense yellow colour, which is a sign of hemolytic jaundice. [ 31 ]


Multiple tests can be used to diagnose  jaundice , but results of different parameters must be compared to determine its  etiology . [ 10 ]


When a patient shows signs of  jaundice  such as the yellowing of the  skin  and  sclera , a  urine test  is performed to check the levels of  urobilinogen  present. [ 32 ]  The presence of  urobilinogen  and its increased levels indicate that there are more than normal amounts of  bilirubin  in the  intestine , showing that  jaundice  observed is not due to the blockage of bile flow, and is of pre-hepatic or hepatic causes. [ 32 ]  Normal colour of the patient's  urine  indicates the absence of unconjugated  bilirubin . [ 27 ]


Results from the urine test should be confirmed by a  complete blood count  (CBC) and serum testing for total serum bilirubin and fractionated bilirubin. [ 32 ]  Increased  reticulocytes  and the presence of  schistocytes  in the  blood smear  of the patient observed during CBC indicates  hemolysis . [ 28 ]  If the patient has hemolytic jaundice, serum testing will show that conjugated bilirubin will only account for less than 15% of the total serum bilirubin due to the increase of unconjugated bilirubin. [ 33 ]


Analysis of liver biopsies will show the levels of  alkaline phosphatase ,  aspartate transaminase , and  alanine transaminase  in the patient, which has a negative correlation with liver function. [ 27 ]  Normal levels of these enzymes indicate that there is no significant hepatocellular damage. [ 27 ]


When an  infant  is suspected to have hemolytic jaundice, abnormal  morphologies  of  erythrocytes  can be analyzed to find out the causes of  hemolysis . [ 34 ]  A  Coomb's test  should be performed, and end-tidal  carbon monoxide  concentration should be monitored to understand the rate of  hemolysis  in the infant's body. [ 35 ]  If chronic hemolytic jaundice is diagnosed in a newborn, development of  anemia  and bilirubin cholelithiasis should be monitored as well. [ 34 ]


If other symptoms of anemia is present, the amount of serum  haptoglobin  in the patient can be measured to test for  hemolysis . [ 36 ]  During  hemolysis ,  hemoglobin  in  blood  dissociates and forms complexes with  haptoglobins  in the plasma, which are then catabolized. [ 37 ]  Low levels of  haptoglobin  resulting from the test shows that there are large amounts of  free hemoglobin  in the  blood  to be bound, acting as an indicator of  hemolysis . [ 36 ]


As  jaundice  is not common in adults, most treatment methods for this condition are centered around  neonates , of which 50% develop  jaundice . [ 27 ] [ 38 ]


Intensive  phototherapy  at saturation dose is used as a first-line clinical treatment which decreases the amount of accumulated unconjugated  bilirubin  in the infant's serum by the addition of  oxygen , thus allowing it to dissolve in  water  so the  liver  can more easily convert it into products which can be  excreted  without further  metabolism . [ 38 ]  For infants with hemolytic jaundice, severe and prolonged cases of  hyperbilirubinemia , or high serum  bilirubin  that does not decrease after  phototherapy ,  blood exchange transfusion  is carried out at the  umbilical venous catheter  to mechanically remove  bilirubin . [ 38 ] [ 39 ] [ 40 ]  In cases of immune hemolytic jaundice,  intravenous immunoglobulin therapy  may be used to treat the condition. [ 41 ]  Administration of  intravenous immunoglobulin  can block monocyte  Fc-receptors , preventing or reducing further  hemolysis . [ 11 ]


In adults, hemolytic jaundice is uncommon, and medical treatment methods should be determined by recognizing the underlying causes of  hemolysis  in the patient. [ 42 ]


In cases where patients receive poor or no treatment of  jaundice , neurodevelopmental complications may follow the condition, eventually leading to  hearing loss ,  visual impairment , and in severe cases, mortality. [ 38 ]


Hyperbilirubinemia  may be observed when  hemolysis  produces too much  bilirubin  through the excessive breakdown of  red blood cells , and the  bilirubin  builds up in the patient's  blood  and  tissue fluids  without proper  excretion . [ 43 ]  Untreated or inadequately treated  hyperbilirubinemia  will lead to other complications such as  kernicterus . [ 12 ]


Chronic bilirubin encephalopathy , also known as  kernicterus , is a brain-damaging complication associated with both  preterm  and  full term  infants with  jaundice , where the large amounts of unconjugated  bilirubin  in the infants become  neurotoxic . [ 39 ] [ 44 ]   Kernicterus  affects mainly the  basal ganglia , and its effects can spread to the  hippocampus ,  geniculate nuclei , and  cranial nerve nuclei . [ 13 ]  Symptoms of  kernicterus  include  athetoid cerebral palsy  and in severe cases, may lead to death of the patient. [ 39 ]  Most cases of  kernicterus  develop in infants following early hospital discharge from  phototherapy . [ 44 ]


Hemolytic–uremic syndrome  ( HUS ) is a group of  blood disorders  characterized by  low red blood cells ,  acute kidney injury  (previously called acute renal failure), and  low platelets . [ 1 ] [ 3 ]  Initial symptoms typically include  bloody diarrhea ,  fever ,  vomiting , and weakness. [ 1 ] [ 2 ]  Kidney problems and low platelets then occur as the diarrhea progresses. [ 1 ]  Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. [ 6 ]  Adults, especially the elderly, may show a more complicated presentation. [ 2 ] [ 6 ]  Complications may include  neurological problems  and  heart failure . [ 1 ]


Most cases occur after  infectious diarrhea  due to a specific type of  E. coli  called  O157:H7 . [ 2 ]  Other causes include  S. pneumoniae ,  Shigella ,  Salmonella , and certain medications. [ 1 ] [ 2 ] [ 3 ]  The underlying mechanism typically involves the production of  Shiga toxin  by the bacteria. [ 1 ] [ 2 ]   Atypical hemolytic uremic syndrome  (aHUS) is often due to a  genetic mutation  and presents differently. [ 1 ] [ 2 ]  However, both can lead to widespread  inflammation  and multiple  blood clots  in small  blood vessels , a condition known as  thrombotic microangiopathy . [ 7 ]


Treatment involves  supportive care  and may include  dialysis ,  steroids ,  blood transfusions , or  plasmapheresis . [ 1 ] [ 2 ]  About 1.5 per 100,000 people are affected per year. [ 5 ] [ 1 ]  Less than 5% of those with the condition die. [ 1 ]  Of the remainder, up to 25% have ongoing kidney problems. [ 1 ]  HUS was first defined as a  syndrome  in 1955. [ 1 ] [ 8 ]


After eating contaminated food, the first symptoms of infection can emerge anywhere from 1 to 10 days later, but usually after 3 to 4 days. [ 9 ]  These early symptoms can include diarrhea (which is often bloody), stomach cramps, mild fever, [ 10 ]  or vomiting that results in dehydration and reduced urine. [ 9 ]  HUS typically develops about 5–10 days after the first symptoms, but can take up to 3 weeks to manifest, and occurs at a time when the diarrhea is improving. [ 10 ]  Related symptoms and signs include lethargy,  decreased urine output ,  blood in the urine ,  kidney failure ,  low platelets , (which are needed for blood clotting), and destruction of red blood cells ( microangiopathic hemolytic anemia ).  High blood pressure ,  jaundice  (a yellow tinge in skin and the whites of the eyes), seizures, and bleeding into the skin can also occur. [ 10 ]  In some cases, there are prominent neurologic changes. [ 11 ] [ 12 ] [ 13 ]


People with HUS commonly exhibit the symptoms of  thrombotic microangiopathy  (TMA), which can include abdominal pain, [ 14 ]  low platelet count, [ 15 ]  elevated  lactate dehydrogenase  LDH, (an enzyme released from damaged cells, and which is therefore a marker of cellular damage) [ 16 ]  decreased haptoglobin (indicative of the breakdown of red blood cells) [ 16 ]  anemia (low red blood cell count), schistocytes (damaged red blood cells), [ 15 ] [ 16 ]  elevated creatinine (a protein waste product generated by muscle metabolism and eliminated renally), [ 17 ]  proteinuria (indicative of kidney injury), [ 18 ]  confusion, [ 14 ]  fatigue, [ 19 ]   swelling , [ 20 ]  nausea/vomiting, [ 21 ]  and diarrhea. [ 22 ]  Additionally, patients with aHUS typically present with an abrupt onset of systemic signs and symptoms such as acute kidney failure, [ 15 ]   hypertension  (high blood pressure), [ 19 ]  myocardial infarction (heart attack), [ 23 ]  stroke, [ 14 ]  lung complications, [ 23 ]   pancreatitis  (inflammation of the pancreas), [ 21 ]  liver necrosis (death of liver cells or tissue), [ 15 ] [ 19 ]   encephalopathy  (brain dysfunction), [ 19 ]  seizure, [ 24 ]  and coma. [ 25 ]  Failure of neurologic, cardiac, renal, 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. [ 5 ] [ 7 ] [ 15 ] [ 18 ] [ 26 ]


Shiga-toxin producing E. coli  (STEC) HUS occurs after ingestion of a strain of bacteria expressing  Shiga toxin  such as enterohemorrhagic  Escherichia coli  (EHEC), of which  E. coli O157:H7  is the most common  serotype . [ 27 ]


Atypical HUS (aHUS) represents 5–10% of HUS cases [ 5 ]  and is largely due to one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of the  complement system , [ 5 ]  which is a group of immune signaling factors that promote inflammation, enhance the ability of  antibodies  and  phagocytic cells  to clear microbes and damaged cells from the body, and directly attack the pathogen's cell membrane. This results in  platelet  activation,  endothelial cell  damage, 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 ultimately death. [ 7 ] [ 18 ] [ 28 ]  Early signs of systemic complement-mediated TMA include  thrombocytopenia  (platelet count below 150,000 or a decrease from baseline of at least 25%) [ 16 ]  and evidence of microangiopathic hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased hemoglobin (the oxygen-containing component of blood), and/or the presence of schistocytes. [ 7 ] [ 29 ] [ 16 ]  Despite the use of supportive care, an estimated 33–40% of patients will die or have  end-stage renal disease  (ESRD) with the first clinical manifestation of aHUS, [ 22 ] [ 23 ]  and 65% of patients will die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI) therapy. [ 22 ]  Patients who survive the presenting signs and symptoms of aHUS endure a chronic thrombotic and inflammatory state, which puts them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death. [ 29 ] [ 20 ]


Historically, treatment options for aHUS were limited to  plasma exchange  or plasma infusion (PE/PI) therapy, which carries significant risks [ 30 ] [ 31 ]  and has not been proven effective in any controlled trials. People with aHUS and ESRD have also had to undergo lifelong dialysis, which has a 5-year survival rate of 34–38%. [ 32 ] [ 33 ]


HUS is caused by ingestion of bacteria that produce  Shiga toxins , with Shiga-toxin producing E. coli (STEC) being the most common type. [ 34 ]   E. coli  can produce shigatoxin-1, shigatoxin-2, or both; with shigatoxin-2 producing organisms being more virulent and being much more likely to cause HUS. [ 34 ]  Once ingested, the bacteria move to the intestines where they produce the Shiga toxins. The bacteria and toxins damage the mucosal lining of the intestines, and thus are able to gain entry into the circulation. [ 34 ]  Shiga toxin enters the mesenteric microvasculature lining the intestines where it releases inflammatory cytokines including  IL-6 ,  IL-8 ,  TNFα , and  IL-1β . [ 34 ]  These inflammatory mediators lead to inflammation and vascular injury with microthrombi that are seen with HUS. It also further damages the intestinal barrier leading to diarrhea (usually bloody) and further entry of Shiga toxin from the intestines to the bloodstream as the intestinal barrier is compromised. [ 34 ]


Once Shiga toxin enters the circulation it can travel throughout the body and cause the wide array of end organ damage and the multitude of symptoms seen with HUS. Shiga toxin gains entry to cells by binding to  globotriaosylceramide  (Gb3) which is a  globoside  found on cell membranes, it is found throughout the body including the surface of the glomerular endothelium of the kidney. [ 35 ]  Shiga toxin gains entry to the cell via Gb3 and  endocytosis , it then is transported to the  Golgi apparatus  where  furin  cleaves the A subunit of the Shiga toxin. [ 34 ]  It is then transported to the  endoplasmic reticulum  where it is further cleaved, leaving the A1 subunit of Shiga toxin free. The A1 subunit of Shiga toxin inhibits the  28s subunit  of the ribosomal  rRNA , this leads to inhibited protein production by the ribosomes. [ 34 ]  With the cell's protein synthesis inhibited by Shiga toxin, the cell is destroyed. [ 34 ]  This leads to vascular injury (including in the kidneys where Gb3 is concentrated). The vascular injury facilitates the formation of vascular microthrombi which are characteristic of TTP. [ 34 ]  The TTP leads to platelet trapping (and thrombocytopenia), red blood cell destruction (and anemia), and end organ damage that is characteristically seen with HUS and TTP. [ 34 ]


HUS is one of the  thrombotic microangiopathies , a category of disorders that includes STEC-HUS, aHUS, and  thrombotic thrombocytopenic purpura  (TTP). The release of  cytokines  and  chemokines  (IL-6, IL-8, TNF-α, IL-1β) that are commonly released by Shiga toxin are implicated in platelet activation and TTP. [ 36 ]  The presence of schistocytes is a key finding that helps to diagnose HUS.


Shiga-toxin directly activates the alternative complement pathway and also interferes with complement regulation by binding to complement factor H, an inhibitor of the complement cascade.  Shiga-toxin causes complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis. [ 37 ] [ 38 ] [ 39 ]  Severe clinical complications of TMA have been reported in patients from 2 weeks to more than 44 days after presentation with STEC-HUS, with improvements in clinical condition extending beyond this time frame, suggesting that complement activation persists beyond the acute clinical presentation and for at least 4 months. [ 40 ]


The consumption of platelets as they adhere to the thrombi lodged in the small vessels typically leads to mild or moderate thrombocytopenia with a platelet count of less than 60,000 per microliter. [ 41 ]  As in the related condition TTP, reduced blood flow through the narrowed blood vessels of the  microvasculature  leads to reduced blood flow to vital organs, and  ischemia  may develop. [ 11 ]  The  kidneys  and the  central nervous system  (brain and spinal cord) are the parts of the body most critically dependent on high blood flow, and are thus the most likely organs to be affected. However, in comparison to TTP, the kidneys tend to be more severely affected in HUS, and the central nervous system is less commonly affected. [ 42 ]


In contrast with typical  disseminated intravascular coagulation  seen with other causes of  sepsis  and occasionally with advanced cancer,  coagulation factors  are not consumed in HUS (or TTP) and the  coagulation screen ,  fibrinogen  level, and assays for  fibrin degradation products  such as "D-Dimers", are generally normal despite the low platelet count (thrombocytopenia). [ 42 ]


HUS occurs after 3–7% of all sporadic  E. coli  O157:H7 infections and up to approximately 20% or more of epidemic infections. [ 43 ]  Children and adolescents are commonly affected. [ 44 ]  One reason could be that children have more Gb3 receptors than adults which may be why children are more susceptible to HUS. Cattle, swine, deer, and other mammals do not have GB3 receptors, but can be asymptomatic carriers of Shiga toxin-producing bacteria. Some humans can also be asymptomatic carriers. Once the bacteria colonizes, diarrhea followed by bloody  diarrhea , hemorrhagic colitis, typically follows. Other serotypes of STEC also cause disease, inlduding HUS, as occurred with  E. coli  O104:H4, which triggered a 2011 epidemic of STEC-HUS in  Germany . [ 45 ]


Grossly, the kidneys may show patchy or diffuse  renal cortical necrosis .  Histologically , the  glomeruli  show thickened and sometimes split capillary walls due largely to endothelial swelling. Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the  mesangium  are also found along with mesangiolysis. Interlobular and afferent arterioles show fibrinoid necrosis and intimal  hyperplasia  and are often occluded by thrombi. [ 12 ]


STEC-HUS most often affects infants and young children, but also occurs in adults. The most common form of transmission is ingestion of undercooked meat, unpasteurized fruits and juices, contaminated produce, contact with unchlorinated water, and person-to-person transmission in daycare or long-term care facilities. [ 25 ]


Unlike typical HUS, aHUS does not follow STEC infection and is thought to result from one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of complement. [ 5 ]  This leads to  platelet  activation,  endothelial cell  damage, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count,  hemolysis , damage to multiple organs, and ultimately, death. [ 7 ] [ 18 ] [ 28 ]  Early signs of systemic complement-mediated TMA include  thrombocytopenia  (platelet count below 150,000 or a decrease from baseline of at least 25%) [ 16 ]  and evidence of  microangiopathic  hemolysis, which is characterized by elevated LDH levels, decreased haptoglobin, decreased  hemoglobin , and/or the presence of schistocytes. [ 7 ] [ 29 ] [ 16 ]


The similarities between HUS, aHUS, and TTP make differential diagnosis essential. [ 7 ] [ 29 ]  All three of these systemic TMA-causing diseases are characterized by thrombocytopenia [ 16 ]  and microangiopathic hemolysis, [ 5 ] [ 16 ]  plus one or more of the following: neurological symptoms (e.g., confusion, [ 5 ] [ 24 ]  cerebral convulsions, [ 24 ]  seizures [ 21 ] ); renal impairment [ 16 ]  (e.g., elevated creatinine, [ 17 ]  decreased estimated glomerular filtration rate [eGFR], [ 17 ]  abnormal urinalysis [ 46 ] ); and gastrointestinal (GI) symptoms (e.g., diarrhea, [ 19 ] [ 22 ]  nausea/vomiting, [ 21 ]  abdominal pain, [ 21 ]  gastroenteritis [ 16 ] [ 19 ] ).The presence of diarrhea does not exclude aHUS as the cause of TMA, as 28% of patients with aHUS present with diarrhea and/or gastroenteritis. [ 18 ] [ 19 ]  First diagnosis of aHUS is often made in the context of an initial, complement-triggering infection, and Shiga-toxin has also been implicated as a trigger that identifies patients with aHUS. [ 40 ]  Additionally, in one study, mutations of genes encoding several complement regulatory proteins were detected in 8 of 36 (22%) patients diagnosed with STEC-HUS. [ 47 ]  However, the absence of an identified complement regulatory gene mutation does not preclude aHUS as the cause of the TMA, as approximately 50% of patients with aHUS lack an identifiable mutation in complement regulatory genes. [ 19 ]