There have been reports of pulmonary venous thromboembolism in pregnant women with sickle cell trait, or men during prolonged airflight, and mild strokes and abnormalities on PET scans in children with the trait.

Sickle cell trait appears to worsen the complications seen in diabetes mellitus type 2 (retinopathy, nephropathy and proteinuria) and provoke hyperosmolar diabetic coma nephropathy, especially in male patients.

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India and the Middle-East. Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle-cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis. In 2015, it resulted in about 114,800 deaths.

Sickle-cell disease occurs more commonly among people whose ancestors lived in tropical and sub-tropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle-cell allele (trait) confers a selective advantage—in other words, being a heterozygote is advantageous. Specifically, humans with one of the two alleles of sickle-cell disease show less severe symptoms when infected with malaria.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The management of an acute event of vaso-occlusive crisis is the use of potent analgesics (opioids), rehydration with normal saline or Ringer's lactate, treatment of malaria (whether symptomatic or not) using artemisinin combination therapy, and the use of oxygen via face mask, especially for acute chest syndrome. Hyperbaric oxygen has also been shown to be a useful adjunct in pain reduction. Antibiotics may be utilized because patients usually have occult infection due to a "functional asplenia".

Sickle-cell anaemia can lead to various complications, including:

- Increased risk of severe bacterial infections due to loss of functioning spleen tissue (and comparable to the risk of infections after having the spleen removed surgically). These infections are typically caused by encapsulated organisms such as "Streptococcus pneumoniae" and "Haemophilus influenzae". Daily penicillin prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for "S. pneumoniae".

- Stroke, which can result from a progressive narrowing of blood vessels, prevents oxygen from reaching the brain. Cerebral infarction occurs in children and cerebral haemorrhage in adults.

- Silent stroke causes no immediate symptoms, but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. About 10–15% of children with SCD suffer strokes, with silent strokes predominating in the younger patients.

- Cholelithiasis (gallstones) and cholecystitis may result from excessive bilirubin production and precipitation due to prolonged haemolysis.

- Avascular necrosis (aseptic bone necrosis) of the hip and other major joints may occur as a result of ischaemia.

- Decreased immune reactions due to hyposplenism (malfunctioning of the spleen)

- Priapism and infarction of the penis

- Osteomyelitis (bacterial bone infection), the most common cause of osteomyelitis in SCD is "Salmonella" (especially the atypical serotypes "Salmonella typhimurium, Salmonella enteritidis, Salmonella choleraesuis" and "Salmonella paratyphi" B), followed by "Staphylococcus aureus" and Gram-negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction.

- Acute papillary necrosis in the kidneys

- Leg ulcers

- In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages, and retinal detachments can result in blindness. Regular annual eye checks are recommended.

- During pregnancy, intrauterine growth retardation, spontaneous abortion, and pre-eclampsia

- Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have unreported chronic pain.

- Pulmonary hypertension (increased pressure on the pulmonary artery) can lead to strain on the right ventricle and a risk of heart failure; typical symptoms are shortness of breath, decreased exercise tolerance, and episodes of syncope. 21% of children and 30% of adults have evidence of pulmonary hypertension when tested; this is associated with reduced walking distance and increased mortality.

- Chronic kidney failure due to sickle-cell nephropathy manifests itself with hypertension, protein loss in the urine, loss of red blood cells in urine and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.

A vaso-occlusive crisis is a common painful complication of sickle cell anemia in adolescents and adults. It is a form of sickle cell crisis. Sickle cell anemia – most common in those of African, Hispanic, and Mediterranean origin – leads to sickle cell crisis when the circulation of blood vessels is obstructed by sickled red blood cells, causing ischemic injuries. The most common complaint is of pain, and recurrent episodes may cause irreversible organ damage. One of the most severe forms is the acute chest syndrome which occurs as a result of infarction of the lung parenchyma. This can rapidly result in death. Other types of vaso-occlusive crisis in sickle cell anemia include dactylitis, priapism, abdominal pain, and jaundice.

Sickle cell trait provides a survival advantage over people with normal hemoglobin in regions where malaria is endemic. The trait is known to cause significantly fewer deaths due to malaria, especially when "Plasmodium falciparum" is the causative organism. This is a prime example of natural selection, evidenced by the fact that the geographical distribution of the gene for hemoglobin S and the distribution of malaria in Africa virtually overlap. Because of the unique survival advantage, people with the trait become increasingly numerous as the number of malaria-infected people increases. Conversely, people who have normal hemoglobin tend to succumb to the complications of malaria.

Although the precise mechanism for this phenomenon is not known, a several factors are believed to be responsible.

- Infected erythrocytes (red blood cells) tend to have lower oxygen tension, because it is significantly reduced by the parasite. This causes sickling of that particular erythrocyte, signalling the phagocytes to get rid of the cell and hence the parasite within.

- Since the sickling of parasite-infected cells is higher, these selectively get removed by the reticulo-endothelial system, thus sparing the normal erythrocytes.

- Excessive vacuole formation occurs in those parasites infecting sickle cells.

- Sickle trait erythrocytes produce higher levels of the superoxide anion and hydrogen peroxide than normal erythrocytes do, both are toxic to malarial parasites.

The sickle cell trait was found to be 50% protective against mild clinical malaria, 75% protective against admission to the hospital for malaria, and almost 90% protective against severe or complicated malaria.

It may result in death, and it is one of the most common causes of death for people with sickle cell anemia.

Inherited mutations in three genes which all result in increased stability of hypoxia-inducible factors, leading to increased erythropoietin production, have been shown to cause erythrocytosis:

- Chuvash polycythemia is an autosomal recessive form of erythrocytosis which is endemic in patients from Chuvashia, an autonomous republic within the Russian Federation. Chuvash polycythemia is associated with homozygosity for a C598T mutation in the von Hippel-Lindau gene ("VHL"), which is needed for the destruction of hypoxia-inducible factors in the presence of oxygen. Clusters of patients with Chuvash polycythemia have been found in other populations, such as on the Italian island of Ischia, located in the Bay of Naples.

- PHD2 erythrocytosis: Heterozygosity for loss-of-function mutations of the "PHD2" gene are associated with autosomal dominant erythrocytosis and increased hypoxia-inducible factors activity.

- HIF2α erythrocytosis: Gain-of-function mutations in" HIF2α "are associated with autosomal dominant erythrocytosis and pulmonary hypertension.

Secondary polycythemia is caused by either natural or artificial increases in the production of erythropoietin, hence an increased production of erythrocytes. In secondary polycythemia, 6 to 8 million and occasionally 9 million erythrocytes may occur per millimeter of blood. Secondary polycythemia resolves when the underlying cause is treated.

Secondary polycythemia in which the production of erythropoietin increases appropriately is called physiologic polycythemia.

Conditions which may result in a physiologically appropriate polycythemia include:

- Altitude related - This physiologic polycythemia is a normal adaptation to living at high altitudes (see altitude sickness). Many athletes train at high altitude to take advantage of this effect — a legal form of blood doping. Some individuals believe athletes with primary polycythemia may have a competitive advantage due to greater stamina. However, this has yet to be proven due to the multifaceted complications associated with this condition.

- Hypoxic disease-associated - for example in cyanotic heart disease where blood oxygen levels are reduced significantly, may also occur as a result of hypoxic lung disease such as COPD and as a result of chronic obstructive sleep apnea.

- Iatrogenic - Secondary polycythemia can be induced directly by phlebotomy (blood letting) to withdraw some blood, concentrate the erythrocytes, and return them to the body.

- Genetic - Heritable causes of secondary polycythemia also exist and are associated with abnormalities in hemoglobin oxygen release. This includes patients who have a special form of hemoglobin known as Hb Chesapeake, which has a greater inherent affinity for oxygen than normal adult hemoglobin. This reduces oxygen delivery to the kidneys, causing increased erythropoietin production and a resultant polycythemia. Hemoglobin Kempsey also produces a similar clinical picture. These conditions are relatively uncommon.

Conditions where the secondary polycythemia is not as a result of physiologic adaptation and occurs irrespective of body needs include:

- Neoplasms - Renal-cell carcinoma or liver tumors, von Hippel-Lindau disease, and endocrine abnormalities including pheochromocytoma and adrenal adenoma with Cushing's syndrome.

- People whose testosterone levels are high because of the use of anabolic steroids, including athletes who abuse steroids, or people on testosterone replacement for hypogonadism or transgender hormone replacement therapy, as well as people who take erythropoietin, may develop secondary polycythemia.

Limiting some microbes' access to iron can reduce their virulence, thereby potentially reducing the severity of infection. Blood transfusion to patients with anemia of chronic disease is associated with a higher mortality, supporting the concept.

A potential complication that may occur in children that suffer acute anemia with a hemoglobin count below 5.5 g/dl is silent stroke A silent stroke is a type of stroke that does not have any outward symptoms (asymptomatic), and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms a silent stroke still causes damage to the brain, and places the patient at increased risk for both transient ischemic attack and major stroke in the future.

A moderate degree of iron-deficiency anemia affects approximately 610 million people worldwide or 8.8% of the population. It is slightly more common in females (9.9%) than males (7.8%). Mild iron deficiency anemia affects another 375 million.

The prevalence of iron deficiency as a cause of anemia varies among countries; in the groups in which anemia is most common, including young children and a subset of non-pregnant women, iron deficiency accounts for a fraction of anemia cases in these groups ("25% and 37%, respectively"). Iron deficiency is a more common cause of anemia in other groups, including pregnant women.

Within the United States, iron-deficiency anemia affects about 2% of adult males, 10.5% of Caucasian women, and 20% of African-American and Mexican-American women.

Hydroxyurea is a medication that can help to prevent acute chest syndrome. It may cause a low white blood cell count, which can predispose the person to some types of infection.

The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely possible.

Parenteral iron is increasingly used for anemia in chronic renal disease and inflammatory bowel disease.

Erythropoietin can be helpful, but this is costly and may be dangerous. Erythropoietin is advised either in conjunction with adequate iron replacement which in practice is intravenous, or when IV iron has proved ineffective.

Blood contains iron within red blood cells, so blood loss leads to a loss of iron. There are several common causes of blood loss. Women with menorrhagia (heavy menstrual periods) are at risk of iron-deficiency anemia because they are at higher-than-normal risk of losing a larger amount blood during menstruation than is replaced in their diet. Slow, chronic blood loss within the body — such as from a peptic ulcer, angiodysplasia, a colon polyp or gastrointestinal cancer, or excessively heavy periods — can cause iron-deficiency anemia. Gastrointestinal bleeding can result from regular use of some groups of medication, such as NSAIDs (e.g. aspirin), as well as anticoagulants such as clopidogrel and warfarin; however, these are required in some patients, especially those with states causing thrombophilia.

Reticulocytopenia, also known as an "aplastic crisis" or "marrow failure", is the medical term for an abnormal decrease of reticulocytes in the body. Reticulocytes are immature red blood cells. Reticulocytopenia may be a result of viral parvovirus B19 infection, which invades and destroys red blood cell precursors and halts the red cell production. If infection occurs in individuals with sickle cell anemia, spherocytosis, or Beta thalassemia that will lead to incorporation of two anemia-induced mechanisms: decreased red cell production and hemolysis. The result is a rapid and severe anemia (aplastic crisis) which may require blood transfusion.

Hemoglobin C gene is found in 2-3% of US African-Americans while 8% of US African \-Americans have hemoglobin S (Sickle) gene. Thus Hemoglobin SC disease is significantly more common than Hemoglobin CC disease. Hemoglobin C is found in areas of West Africa, such as Nigeria, where Yorubas live.

About 1 out of every 40 African-Americans has hemoglobin C trait. The trait also affects people whose ancestors came from Italy, Greece, Africa, Latin America, and the Caribbean region. 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. Hemoglobin C disease is present at birth, though some cases may not be diagnosed until adulthood. Both sexes, male and female, are affected equally.

G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for acquiring ischemic heart disease and cerebrovascular disease.

Overall, hemoglobin C disease is one of the more benign hemoglobinopathies. 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. People with hemoglobin C disease can expect to lead a normal life.

There was a study on a three year old that was a carrier of the hemoglobin variant of Hopkins-2. The child had mild anemia and reticulocytosis, which is commonly seen in anemia. There were, however, no sickled cells found in the blood and they had no symptoms relating to sickle cell. There was also a reduced mean corpuscular volume (MCV), which is the average volume of red blood cell count.

Those homozygous (Hb LeporeLepore; a very rare situation) or compound heterozygous (Hb Lepore-Β-thalassaemia) might suffer from a severe anaemia. They should be managed in a comprehensive multi-disciplinary program of care. Management includes a regular course of blood transfusions, although the clinical severity in compound (double) heterozygotes can range from minor to major, depending on the combination of genes that have caused the condition.

In terms of epidemiology, worldwide distribution of inherited alpha-thalassemia corresponds to areas of malaria exposure, suggesting a protective role. Thus, alpha-thalassemia is common in sub-Saharan Africa, the Mediterranean Basin, and generally tropical (and subtropical) regions. The epidemiology of alpha-thalassemia in the US reflects this global distribution pattern. More specifically, HbH disease is seen in Southeast Asia and the Middle East, while Hb Bart hydrops fetalis is acknowledged in Southeast Asia only.

The data indicate that 15% of the Greek and Turkish Cypriots are carriers of beta-thalassaemia genes, while 10% of the population carry alpha-thalassaemia genes.

There were five carriers of Hemoglobin Hopkins 2 in the Fuller-Carr family and ten double heterozygotes of Ho-2 and Hemoglobin S. All the carriers were in good health and had normal hematology test results. Out of those carrying hemoglobin S and Ho-2, none were anemic; but, a few of those studied displayed elevated reticulocyte counts. This is measured through a blood test that analyzes the speed of production of red blood cells by bone marrow and its release into the blood. There was no suggestion of symptomatic sickle cell anemia in the family.

G6PD deficiency is the second most common human enzyme defect after ALDH2 deficiency, being present in more than 400 million people worldwide. G6PD deficiency resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990. African, Middle Eastern and South Asian people are affected the most, including those who have these ancestries. A side effect of this disease is that it confers protection against malaria, in particular the form of malaria caused by "Plasmodium falciparum", the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. One theory to explain this is that cells infected with the "Plasmodium" parasite are cleared more rapidly by the spleen. This phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments.

In vitro studies have shown that the "Plasmodium falciparum" is very sensitive to oxidative damage. This is the basis for another theory, that is that the genetic defect confers resistance due to the fact that the G6PD-deficient host has a higher level of oxidative agents that, while generally tolerable by the host, are deadly to the parasite.

Preterm infants are often anemic and typically experience heavy blood losses from frequent laboratory testing in the first few weeks of life. Although their anemia is multifactorial, repeated blood sampling and reduced erythropoiesis with extremely low serum levels of erythropoietin (EPO) are major determining factors. Blood sampling done for laboratory testing can easily remove enough blood to produce anemia. Obladen, Sachsenweger and Stahnke (1987) studied 60 very low birth weight infants during the first 28 days of life. Infants were divided into 3 groups, group 1 (no ventilator support, 24 ml/kg blood loss), group 2(minor ventilated support, 60 ml/kg blood loss), and group 3(ventilated support for respiratory distress syndrome, 67 ml/kg blood loss). Infants were checked for clinical symptoms and laboratory signs of anemia 24 hours before and after the blood transfusion. The study found that groups 2 and 3 who had significant amount of blood loss, showed poor weight gain, pallor and distended abdomen. These reactions are the most frequent symptoms of anemia.

During the first weeks of life, all infants experience a decline in circulating red blood cell (RBC) volume generally expressed as blood hemoglobin concentration (Hb). As anemia develops, there is even more of a significant reduction in the concentration of hemoglobin. Normally this stimulates a significant increased production of erythropoietin (EPO), but this response is diminished in premature infants. Dear, Gill, Newell, Richards and Schwarz (2005) conducted a study to show that there is a weak negative correlation between EPO and Hb. The researchers recruited 39 preterm infants from 10 days of age or as soon as they could manage without respiratory support. They estimated total EPO and Hb weekly and 2 days after a blood transfusion. The study found that when Hb>10, EPO mean was 20.6 and when Hb≤10, EPO mean was 26.8. As Hb goes down, EPO goes up. While the reason for this decreased response is not fully understood, Strauss (n.d.) states that it results from both physiological factors (e.g., the rapid rate of growth and need for a commensurate increase in RBC mass to accompany the increase in blood volume) and, in sick premature infants, from phlebotomy blood losses. In premature infants this decline occurs earlier and more pronounced that it does in healthy term infants. Healthy term infants Hb rarely falls below 9 g/dL at an age of approximately 10–12 weeks, while in premature infants, even in those without complicating illnesses, the mean Hb falls to approximately 8g/dL in infants of 1.0-1.5 kg birth weight and to 7g/dL in infants <1.0 kg. Because this postnatal drop in hemoglobin level is universal and is well tolerated in term infants, it is commonly referred to as the “physiologic” anemia of infancy. However, in premature infants the decline in Hb may be associated with abnormal clinical signs severe enough to prompt transfusions.