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.

Those with hereditary elliptocytosis have a good prognosis, only those with very severe disease have a shortened life expectancy.

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.

The incidence of hereditary elliptocytosis is hard to determine, as many sufferers of the milder forms of the disorder are asymptomatic and their condition never comes to medical attention. Around 90% of those with this disorder are thought to fall into the asymptomatic population. It is estimated that its incidence is between 3 and 5 per 10,000 in the United States, and that those of African and Mediterranean descent are of higher risk. Because it can confer resistance to malaria, some subtypes of hereditary elliptocytosis are significantly more prevalent in regions where malaria is endemic. For example, in equatorial Africa its incidence is estimated at 60-160 per 10,000, and in Malayan natives its incidence is 1500-2000 per 10,000. Almost all forms of hereditary elliptocytosis are autosomal dominant, and both sexes are therefore at equal risk of having the condition. The most important exception to this rule of autosomal dominance is for a subtype of hereditary elliptocytosis called hereditary pyropoikilocytosis (HPP), which is autosomal recessive.

There are three major forms of hereditary elliptocytosis: common hereditary elliptocytosis, spherocytic elliptocytosis and southeast Asian ovalocytosis.

Common hereditary elliptocytosis is the most common form of elliptocytosis, and the form most extensively researched. Even when looking only at this form of elliptocytosis, there is a high degree of variability in the clinical severity of its subtypes. A clinically significant haemolytic anaemia occurs only in 5-10% of sufferers, with a strong bias towards those with more severe subtypes of the disorder.

Southeast Asian ovalocytosis and spherocytic elliptocytosis are less common subtypes predominantly affecting those of south-east Asian and European ethnic groups, respectively.

The following categorisation of the disorder demonstrates its heterogeneity:

- Common hereditary elliptocytosis (in approximate order from least severe to most severe)

- With asymptomatic carrier status - "individuals have no symptoms of disease and diagnosis is only able to be made on blood film"

- With mild disease - "individuals have no symptoms, with a mild and compensated haemolytic anaemia"

- With sporadic haemolysis - "individuals are at risk of haemolysis in the presence of particular comorbidities, including infections, and vitamin B deficiency"

- With neonatal poikilocytosis - "individuals have a symptomatic haemolytic anaemia with poikilocytosis that resolves in the first year of life"

- With chronic haemolysis - " individual has a moderate to severe symptomatic haemolytic anaemia (this subtype has variable penetrance in some pedigrees)"

- With homozygosity or compound heterozygosity - "depending on the exact mutations involved, individuals may lie anywhere in the spectrum between having a mild haemolytic anaemia and having a life-threatening haemolytic anaemia with symptoms mimicking those of HPP (see below)"

- With pyropoikilocytosis (HPP) - "individuals are typically of African descent and have a life-threateningly severe haemolytic anaemia with micropoikilocytosis (small and misshapen erythrocytes) that is compounded by a marked instability of erythrocytes in even mildly elevated temperatures (pyropoikilocytosis is often found in burns victims and is the term is commonly used in reference to such people)

- South-east Asian ovalocytosis (SAO) (also called stomatocytic elliptocytosis) - "individuals are of South-East Asian descent (typically Malaysian, Indonesian, Melanesian, New Guinean or Filipino, have a mild haemolytic anaemia, and has increased resistance to malaria"

- Spherocytic elliptocytosis (also called hereditary haemolytic ovalocytosis) - "individuals are of European descent and elliptocytes and spherocytes are simultaneously present in their blood"

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.

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.

About 90% of people survive to age 20, and close to 50% survive beyond the fifth decade. In 2001, according to one study performed in Jamaica, the estimated mean survival for people with sickle-cell was 53 years old for men and 58 years old for women with homozygous SCD. The specific life expectancy in much of the developing world is unknown.

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.

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.

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.

Hemoglobin E is most prevalent in mainland Southeast Asia (Thailand, Myanmar, Cambodia, Laos, Vietnam), where its prevalence can reach 30 or 40%, and Northeast India, where in certain areas carrier rates reach 60% of the population. In Thailand the mutation can reach 50 or 70%, and it is higher in the northeast of the country. In Sri Lanka, it can reach up to 40% and affects those of Sinhalese and Vedda descent. It is also found at high frequencies in Bangladesh and Indonesia. The trait can also appear in people of Turkish, Chinese and Filipino descent. The mutation is estimated to have arisen within the last 5,000 years. In Europe there have been found cases of families with hemoglobin E, but in these cases, the mutation differs from the one found in South-East Asia. This means that there may be different origins of the βE mutation.

Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Hemoglobinopathies are inherited single-gene disorders; in most cases, they are inherited as autosomal co-dominant traits. Common hemoglobinopathies include sickle-cell disease. It is estimated that 7% of world's population (420 million) are carriers, with 60% of total and 70% pathological being in Africa. Hemoglobinopathies are most common in populations from Africa, the Mediterranean basin and Southeast Asia.

Hemoglobinopathies imply structural abnormalities in the globin proteins themselves. Thalassemias, in contrast, usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some hemoglobinopathies are also thalassemias, but most are not.

Either hemoglobinopathy or thalassemia, or both, may cause anemia. Some well-known hemoglobin variants such as sickle-cell anemia and congenital dyserythropoietic anemia are responsible for diseases, and are considered hemoglobinopathies. However, many hemoglobin variants do not cause pathology or anemia, and thus are often not classed as hemoglobinopathies, because they are not considered pathologies. Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Other variants cause no detectable pathology, and are thus considered non-pathological variants.

HPFH may alleviate the severity of certain hemoglobinopathies and thalassemias, and is selected for in populations with a high prevalence of these conditions (which in turn are often selected for in areas where malaria is endemic). Thus, it has been found to affect Americans of African and Greek descent.

Pyruvate kinase deficiency happens worldwide, however northern Europe, and Japan have many cases. The prevalence of pyruvate kinase deficiency is around 51 cases per million in the population (via gene frequency).

People who have hemoglobin E/β-thalassemia have inherited one gene for hemoglobin E from one parent and one gene for β-thalassemia from the other parent. Hemoglobin E/β-thalassemia is a severe disease, and it still has no universal cure. It affects more than a million people in the world. The consequences of hemoglobin E/β-thalassemia when it is not treated can be heart failure, enlargement of the liver, problems in the bones, etc.

There is a variety of genotypes depending on the interaction of HbE and α-thalassemia. The presence of the α-thalassemia reduces the amount of HbE usually found in HbE heterozygotes. In other cases, in combination with certain thalassemia mutations, it provides an increased resistance to malaria ("P. falciparum").

In persons with sickle cell disease, high levels of fetal hemoglobin as found in a newborn or as found abnormally in persons with hereditary persistence of fetal hemoglobin, the HbF causes the sickle cell disease to be less severe. In essence the HbF inhibits polymerization of HbS. A similar mechanism occurs with persons who have sickle cell "trait". Approximately 40% of the hemoglobin is in the HbS form while the rest is in normal HbA form. The HbA form interferes with HbS polymerization.

Some hemoglobinopathies (and also related diseases like glucose-6-phosphate dehydrogenase deficiency) seem to have given an evolutionary benefit, especially to heterozygotes, in areas where malaria is endemic. Malaria parasites live inside red blood cells, but subtly disturb normal cellular function. In patients predisposed for rapid clearance of red blood cells, this may lead to early destruction of cells infected with the parasite and increased chance of survival for the carrier of the trait.

Hemoglobin functions:

- Transport of oxygen from the lungs to the tissues: This is due to the peculiar cooperation of the globin chains that allows the molecule to take in more oxygen where there is increased oxygen and to release oxygen in low concentration of oxygen.

- Transport of carbon dioxide from the tissues to the lungs: The end product of tissue metabolism is acidic which increases hydrogen ions in solution. The hydrogen ions combine with bicarbonates to produce water and carbon dioxide. The carbon dioxide is mop up by hemoglobin to favor this reversible reaction.

- Transport of nitric oxide: Nitric oxide is a vasodilatator. This assists in the regulation of vascular reaction in times of stress as experienced during inflammation.

Pathology and organic structural abnormalities may lead to any of the following disease processes:

- Anemia due to reduced life span of the red cells of reduced production of the cells e. g. hemoglobin S, C and E.

- Increased oxygen affinity: The red blood cells do not release their oxygen content readily in hypoxic conditions. The bone marow therefore needs to produce more red blood cells and there is polycythemia.

- Unstable hemoglobins: Red blood cells are easily destroyed under stress and hemolysis occurs with possible jaundice.

- Methemoglobinemia: The iron in the heme portion of hemoglobin is easily oxidised and this reduces the ability of hemoglobin to bind oxygen. More deoxygenated hemoglobin are formed and the blood becomes cyanotic.

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.

Hemoglobin Hopkins-2 (Hb Hop-2) is a mutation of the protein hemoglobin, which is responsible for the transportation of oxygen through the blood from the lungs to the musculature of the body in vertebrates. Generally, the mutation causes two abnormal α chains in the protein's structure. Within the chains, the mutation is the result of hemoglobin's histidine amino acid being replaced with aspartic acid in the protein's genetic sequence. This amino acid structure change occurs at residue 112. Additionally, within one of the mutated alpha chains, there are substitutes at 114 and 118, two points on the amino acid chain. This mutation can cause sickle cell anemia.

Following the initial discovery of hemoglobin, two researchers working at Johns Hopkins Hospital in the mid-twentieth century, Ernest W. Smith and J.V. Torbert, discovered the Hopkins-2 mutation of hemoglobin. Work by Harvey A. Itano and Elizabeth A. Robinson in 1960 confirmed Smith's and Torbert's finding and emphasized the importance of the alpha loci in the mutation. Later in the twentieth century, Samuel Charache, another Hopkins affiliated scientist and doctor, studied the physiological impacts of the variant on health. His findings suggest that the variant plays no effect clinically.

Most affected individuals with pyruvate kinase deficiency do not require treatment. Those individuals who are more severely affected may die in utero of anemia or may require intensive treatment. With these severe cases of pyruvate kinase deficiency in red blood cells, treatment is the only option, there is no cure. However, treatment is usually effective in reducing the severity of the symptoms.

The most common treatment is blood transfusions, especially in infants and young children. This is done if the red blood cell count has fallen to a critical level. The transplantation of bone marrow has also been conducted as a treatment option.

There is a natural way the body tries to treat this disease. It increases the erythrocyte production (reticulocytosis) because reticulocytes are immature red blood cells that still contain mitochondria and so can produce ATP via oxidative phosphorylation. Therefore, a treatment option in extremely severe cases is to perform a splenectomy. This does not stop the destruction of erythrocytes but it does help increase the amount of reticulocytes in the body since most of the hemolysis occurs when the reticulocytes are trapped in the hypoxic environment of the spleen. This reduces severe anemia and the need for blood transfusions.

A review from 2000 stated that life expectancy was reduced because of a tendency to develop cancer relatively early as well as deaths due to infections related to immunodeficiency.

Absence of effective splenic function or absence of the whole spleen (asplenia) is associated with increased risks of overwhelming post splenectomy infection, especially from polysaccharide encapsulated bacteria and organisms that invade erythrocytes. People without a spleen have a weakened immune system, although other immune organs compensate for the missing spleen. Vaccination against encapsulated bacteria and prophylactic antibiotics can be used to counteract lowered immunity in asplenic patients. Specifically, people without a spleen are recommended to be vaccinated against pneumonia, influenza, Haemophilus influenza type b and meningococci.

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

An autosplenectomy (from" 'auto-' "self," '-splen-' "spleen," '-ectomy' "removal) is a negative outcome of disease and occurs when a disease damages the spleen to such an extent that it becomes shrunken and non-functional. The spleen is an important immunological organ that acts as a filter for red blood cells, triggers phagocytosis of invaders, and mounts an immunological response when necessary. Lack of a spleen, called asplenia, can occur by autosplenectomy or the surgical counterpart, splenectomy. Asplenia can increase susceptibility to infection. Autosplenectomy can occur in cases of sickle-cell disease where the misshapen cells block blood flow to the spleen, causing fibrosis and eventual atrophy of the organ. Autosplenectomy is a rare condition that is linked to certain diseases but is not a common occurrence.

Nijmegen breakage syndrome (NBS), also known as Berlin breakage syndrome, ataxia telangiectasia variant 1 (AT-V1) and Seemanova syndrome, is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA (see Homologous recombination).

NBS1 codes for a protein (nibrin) that has two major functions: (1) to stop the cell cycle in the S phase, when there are errors in the cell DNA (2) to interact with FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair. This explains why mutations in the NBS1 gene lead to higher levels of cancer (see Fanconi anemia, Cockayne syndrome.)

The name derives from the Dutch city Nijmegen where the condition was first described.

Most people with NBS have West Slavic origins. The largest number of them live in Poland.