In HbS, the complete blood count reveals haemoglobin levels in the range of 6–8 g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).

Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.

Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.

An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.

People who are known carriers of the disease often undergo genetic counseling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the fetus or a sample of amniotic fluid. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening provides not only a method of early detection for individuals with sickle-cell disease, but also allows for identification of the groups of people that carry the sickle cell trait.

The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they have thalassemia. Genetic counseling and genetic testing are recommended for families who carry a thalassemia trait.

A screening policy exists in Cyprus to reduce the rate of thalassemia, which, since the program's implementation in the 1970s (which also includes prenatal screening and abortion), has reduced the number of children born with the disease from one of every 158 births to almost zero.

In Iran as a premarital screening, the man's red cell indices are checked first, if he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic, their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.

Large scale awareness campaigns are being organized in India both by government and non-government organizations in favor of voluntary premarital screening to detect carriers of thalassemia and marriage between both carriers are strongly discouraged.

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 diagnosis of delta-beta thalassemia is done via hypochromic microcytic red cell indices. This test is a part of a CBC, and could be employed to diagnose the reason the individual might have anemia, in this case due to thalassemia.

Physical examination may show an enlarged spleen. Tests that may be done include: Complete Blood Count (CBC), Hemoglobin electrophoresis, Peripheral blood smear, and Blood hemoglobin.

From birth to five years of age, penicillin daily, due to the immature immune system that makes them more prone to early childhood illnesses is recommended. Dietary supplementation of folic acid had been previously recommended by the WHO. A 2016 Cochrane review of its use found "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear" due to a lack of medical evidence.

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

Because of the microcirculatory distress, a telltale sign or symptom of a potential sickling collapse is cramping. Specifically to sickle cell trait, cramping occurs in the lower extremities and back in athletes undergoing intense physical activity or exertion. In comparison to heat cramps, sickling cramps are less intense in terms of pain and have a weakness and fatigue associated with them, as opposed to tightly contracted muscles that lock up during heat cramps.

A sickling collapse comes on slowly, following cramps, weakness, general body aches and fatigue. Individuals with known positive sickle cell trait status experiencing significant muscle weakness or fatigue during exercise should take extra time to recover and hydrate before returning to activity in order to prevent further symptoms.

A collapse can be prevented by taking steps to ensure sufficient oxygen levels in the blood. Among these preventative measures are proper hydration and gradual acclimation to conditions such as heat, humidity, and decreased air pressure due to higher altitude. Gradual progression of exertion levels also helps athletes' bodies adjust and compensate, gaining fitness slowly over the course of several weeks.

Thalassemia can coexist with other hemoglobinopathies. The most common of these are:

- Hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India, it is clinically similar to β thalassemia major or thalassemia intermedia.

- Hemoglobin S/thalassemia: common in African and Mediterranean populations, is clinically similar to sickle-cell anemia, with the additional feature of splenomegaly.

- Hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/β thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β thalassemia produces a milder disease.

- Hemoglobin D/thalassemia: common in the northwestern parts of India and Pakistan (Punjab region).

Diagnosis of alpha-thalassemia is primarily by laboratory evaluation and haemoglobin electrophoresis. Alpha-thalassemia can be mistaken for iron-deficiency anaemia on a full blood count or blood film, as both conditions have a microcytic anaemia. Serum iron and serum ferritin can be used to exclude iron-deficiency anaemia.

In terms of treatment for delta-beta thalassemia one possible concern would be anemia, where, therefore, blood transfusions would be given to the affected individual (though blood transfusions might introduce complications, as well).

Stem cell transplant is another option, but the donor and the individual who will receive the bone marrow transplant must be compatible, the risks involved should be evaluated, as well

In general on acid electrophoresis in order of increasing mobility are hemoglobins F, A=D=G=E=O=Lepore, S, and C.

This is how abnormal hemoglobin variants are isolated and identified using these two methods. For example, a Hgb G-Philadelphia would migrate with S on alkaline electrophoresis and would migrate with A on acid electrophoresis, respectively

use of iso electric focusing to determine quantitative differences in globin chain synthesis and high performance liquid chromatography that separates hemoglobins based on their various affinities for the column

In general on alkaline electrophoresis in order of increasing mobility are hemoglobins A2, E=O=C, G=D=S=Lepore, F, A, K, J, Bart's, N, I, and H.

In general a sickling test (sodium bisulfite) is performed on abnormal hemoglobins migrating in the S location to see if the red cells precipitate in solution.

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.

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.

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").

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.

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.

Hemoglobin Barts, abbreviated Hb Barts, is an abnormal type of hemoglobin that consists of four gamma globins. It is moderately insoluble, and therefore accumulates in the red blood cells. It has an extremely high affinity for oxygen, resulting in almost no oxygen delivery to the tissues. As an embryo develops, it begins to produce alpha-globins at weeks 5-6 of development. When both HBA1 and HBA2, the two genes that code for alpha globins, are non-functional, only gamma globins are produced. These gamma globins bind to form hemoglobin Barts. It is produced in the disease alpha-thalassemia and in the most severe of cases, it is the only form of haemoglobin in circulation. In this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth, unless intrauterine blood transfusion is performed.

Since hemoglobin Barts is elevated in alpha thalassaemia, it can be measured, providing a useful screening test for this disease in some populations.

The ability to measure hemoglobin Barts makes it useful in newborn screening tests. If hemoglobin Barts is detected on a newborn screen, the patient is usually referred for further evaluation since detection of hemoglobin Barts can indicate either one alpha globin gene deletion, making the baby a silent alpha thalassemia carrier, two alpha globin gene deletions (alpha thalassemia), or hemoglobin H disease (three alpha globin gene deletions). Deletion of four alpha globin genes is not compatible with life.

This variant of hemoglobin is so called as it was discovered at St. Bartholomew's Hospital in London, also called St. Barts.

The Düsseldorf score stratifies cases using four categories, giving one point for each; bone marrow blasts ≥5%, LDH >200U/L, haemoglobin ≤9g/dL and a platelet count ≤100,000/uL. A score of 0 indicates a low risk group' 1-2 indicates an intermediate risk group and 3-4 indicates a high risk group. The cumulative 2 year survival of scores 0, 1-2 and 3-4 is 91%, 52% and 9%; and risk of AML transformation is 0%, 19% and 54% respectively.

Microcytosis is a condition in which red blood cells are unusually small as measured by their mean corpuscular volume.

It is also known as "microcythemia". When associated with anemia, it is known as microcytic anemia.

Microcytic anemia is not caused by reduced DNA synthesis.

Thalassemia can cause microcytosis. Depending upon how the terms are being defined, thalassemia can be considered a cause of microcytic anemia, or it can be considered a cause of microcytosis but not a cause of microcytic anemia.

There are many causes of microcytosis, which is essentially only a descriptor. Cells can be small because of mutations in the formation of blood cells (hereditary microcytosis) or because they are not filled with enough hemoglobin, as in iron-deficiency-associated microcytosis.

Red blood cells can be characterised by their haemoglobin content as well as by their size. The haemoglobin content is referred to as the cell's colour. Therefore, there are both "normochromic microcytotic red cells" and "hypochromic, microcytotic red cells". The normochromic cells have a normal concentration of haemoglobin, and are therefore 'red enough' while the hypochromic cells do not; thus the value of the mean corpuscular hemoglobin concentration.

Runner’s macrocytosis is a phenomenon of increased red blood cell size as a compensatory mechanism for increased red blood cell turnover. The impact forces from running can lead to red blood cell hemolysis and accelerate red blood cell production. This can shift the ratio of red blood cells towards younger, larger cells. This shift may be reflected in higher than normal mean corpuscular volume (MCV) values, an indicator of red blood cell size.

This is not a pathological condition but may indicate a propensity toward iron deficiency anemia due to high red blood cell turnover.

March hematuria, occurs when blood is seen in the urine after repetitive impacts on the body, particularly affecting the feet. The word "march" is in reference to the condition arising in soldiers who have been marching for long periods; the condition was first documented in 1881.

The International Prognostic Scoring System (IPSS) was developed in the mid-1990s to assess the prognosis of MDS patients. This system stratifies cases into 2 groups; a lower-risk group (sub divided into low and intermediate-1) and a higher risk (subdivided into intermediate-2 and high). It uses the blast percentage, number of cytopaenias and bone marrow cytogenetics data to place cases of CMML into these groups. Due to the scoring system being developed for MDS, the more myeloproliferative cases of CMML (WBC >13x10) are excluded from the scoring system. Although the IPSS scoring system is used clinically, there is a high variability in each group. For this reason, new modalities for assessing prognosis in MDS (and CMML) are being developed.