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The term hemoglobinopathy comprises several genetic disorders leading to defective or insufficient hemoglobin synthesis. Depending on the kind of defects provoked in hemoglobin components and mode of inheritance, clinical consequences may differ.


Although hemoglobinopathies include malformations of the hemoglobin molecule due to different genetic defects, some symptoms may indeed be present in several hemoglobinopathies [5]. These symptoms derive from functional limitations regarding hemoglobin oxygenation and oxygen supply to tissues.

Therefore, it should not come as a surprise that symptomatic cases of hemoglobinopathies usually demonstrate dyspnea and fatigue. The overall deficiency of oxygen may lead to retardation of growth and puberty. Joint, bone and chest pain may be experienced by the patient.

Since hemoglobinopathies often become symptomatic when they trigger hemolysis, a pre-hepatic icterus, hepatomegaly and splenomegaly may be observed. However, hemolysis is not necessarily present in all kinds of hemoglobinopathies. Certain forms may even be accompanied by erythrocytosis, hemoglobinemia and increased hematokrit (please also refer to pathophysiology). Thus, every hemoglobinopathy presents specific symptoms and requires a corresponding workup.

  • Subsequent amputation of the distal portions of all four extremities was necessary because of dry gangrene.[ncbi.nlm.nih.gov]
  • The medium- to large-sized arteries were involved, and in some cases this involvement led to gangrene of the limbs, aneurysm formation, and ultimately fatal arterial leakage. All five patients were farmers.[ncbi.nlm.nih.gov]
  • [email protected] Abstract Hemoglobinopathies are an uncommon cause of cyanosis and low oxygen saturation on pulse oximetry. However, when they do occur, they can present a complex clinical scenario for the emergency physician.[ncbi.nlm.nih.gov]
  • Neonates present with cyanosis but are otherwise clinically well. There is often a family history of neonatal cyanosis that resolves over the first two months of life.[clinicaladvisor.com]
  • […] range Hemoglobin C disease Hemoglobin c trait Hemoglobin D disease Hemoglobin D trait Hemoglobin E disease Hemoglobin e trait Hemoglobin low Hemoglobin O-Arab trait Hemoglobin very high Hemoglobin Zurich disease Hemoglobinopathy Hemoglobinopathy with cyanosis[icd9data.com]
  • Blood levels of deoxygenated hemoglobin increase and give rise to cyanosis. Hb Mobile and Hb Vancouver are examples for this type of hemoglobinopathy.[symptoma.com]
  • Abstract A 27-month-old patient with SOArab hemoglobinopathy complicated by purpura fulminants was studied with 99mTc-pyrophosphate.[ncbi.nlm.nih.gov]
Facial Pain
  • In 6 cases, such lesions were combined with facial pain during sickle cell crisis and absence of dental pathology and were considered to be of possible vasoocclusive origin.[ncbi.nlm.nih.gov]
  • Optimization of wet steps should also be followed by careful and perhaps individualized dye excitation and in silico scoring rules, taking into consideration decay and bleaching effects that perplex development.[ncbi.nlm.nih.gov]
  • METHODS: An online survey of all 137 primary care pediatric providers at a New York City academic medical center was conducted in 2008-2009 to assess practices for hemoglobin-apathy trait follow-up.[ncbi.nlm.nih.gov]


A hemoglobinopathy may be suspected after analyzing the medical history of the patient, realizing a clinical examination and interpreting the results of a blood screening [6]. The medical history is particularly important because hemoglobinopathies are genetic diseases and may thus have been observed in the patient's family. Between quantitative and qualitative hemoglobinopathies and a large number of possible genetic disorders, further diagnostic measures need to be taken to reach an exact diagnosis. The following measures may be considered:

  • Complete blood count including red blood cell morphology and reticulocyte count
  • Protein based analytic measures
  • Chromatographic measures
  • Molecular-biological diagnostics, e.g. PCR, RT-PCR, genomic sequencing

Specific tests may be required to confirm or exclude certain hemoglobinopathies. For instance, instable hemoglobin may form Heinz inclusion bodies that will not be visible in standard stains.

  • Also, increased risk (odds ratio) of albuminuria was noted with SCD, age, anemia, abnormal eGFR, obesity, and ARR.[ncbi.nlm.nih.gov]
  • Microalbuminuria (168.8 /- 59.7 mg/day) was noted in the majority (63.6%) while macroalbuminuria (752.7 /- 205.4 mg/day) was detected in a smaller percentage (36.4%).[ncbi.nlm.nih.gov]
Staphylococcus Aureus
  • Staphylococcus aureus (S. aureus) was isolated from 62% of chronic osteomyelitis (COM) and 58% of pyomyositis, while gram-negative bacilli accounted for 34% and 42%, respectively.[ncbi.nlm.nih.gov]


While mild forms of hemoglobinopathies may not require treatment, some patients suffer from severe anemia and need life-long support. Causal treatment may be given if a stem-cell transplantation is an option. Indeed, if this therapeutic method is available, it is the treatment of choice for severe cases of hemoglobinopathies.

Blood transfusions form part of a symptomatic therapy, as may analgesics, antibiotics, anti-hypertensive drugs and hydroxyurea [7]. This particularly applies to patients suffering from sickle-cell anemia [8] [9].

Secondary hemosiderosis may be treated with transfusions or stem-cell transplantation [10].


Since hemoglobinopathies result from genetic defects, there is no causal therapy. However, only few hemoglobinopathies do actually require treatment. If this is the case, symptomatic treatment may considerably alleviate symptoms. Even people affected by severe hemoglobinopathies have an average life expectancy of 50 to 60 years, if adequately treated. Infancy and pregnancy are those periods of time associated with greatest risks [4].


While thalassemias are characterized by an insufficient synthesis of normal hemoglobin, other genetic disorders impair the synthesis of functional hemoglobin, particularly of functional globin chains, although other components of hemoglobin may also be affected.

Whereas certain genetic defects may provoke severe symptoms, the vast majority of hemoglobinopathies remains undetected because no symptoms are presented at all. Many hemoglobinopathies are detected during routine blood screenings since they are accompanied by hematologic changes.

Genetic defects affect the amino acid composition of proteins. Amino acids may be substituted by another (as is the case in Hb C, Hb S and many other hemoglobinopathies), deleted (e.g., Hb Gun Hill) or even added (e.g., Hb Constant Spring). Furthermore, mutations may lead to abnormal hybridization between two chains (e.g., Hb Lepore). α-, β-, γ- and δ-chains may be affected. In the case of thalassemias, mutations generally affect regulatory genes.

The most severe hemoglobinopathies are Hb C and Hb S, concern the β-globin chains and are associated with hemolysis.


Hemoglobinopathies comprise different genetic disorders that limit hemoglobin synthesis or hinder synthesis of functional hemoglobin and may cause symptoms as severe as hemolysis.

Hb S is associated with sickling disorders, while this is not the case with Hb C. These groups of hemoglobinopathies may be accompanied by hemolysis and are therefore of clinical importance. Of note, hemolysis may be caused by genetic defects that do not affect hemoglobin synthesis but rather erythrocytes themselves. Such is the case with glucose-6-phosphate dehydrogenase deficiency [2].

Homozygous carriers of the sickle cell gene suffer from hemolysis and subsequent anemia. This also applies for people heterozygously carrying both the sickle cell gene and Hb C. The sickle cell gene is most prevalent in Africa and countries with considerable populations of African immigrants, in the Middle East, some Mediterranean countries and subtropical Asia [3]. It has been estimated that about two thirds of more than 400 million carriers worldwide live in Africa. Race should not be considered an exclusion factor for sickling cell disorders or other hemoglobinopathies.

Sex distribution
Age distribution


A variety of missense mutations causes changes in the amino acid composition of the globin chains. And even though hemoglobinopathies are generally characterized by defective globin chains, genetic defects may affect different parts of the protein, different chains, different segments of each chain. An amino acid change at position X may result detrimental, an amino acid change at position Y may turn out insignificant.

The most severe hemoglobinopathies are caused by substitution of glutamate at position 6 of the β-chain by lysine or valine, respectively. This results in Hb C and Hb S synthesis, respectively, and triggers formation of crystals, subsequent hemolysis and even tissue infarction. On the contrary, other hemoglobinopathies (e.g. those involving synthesis of Hb J-Lome and Hb J-Kaoshiung) are also due to amino acid substitutions but remain asymptomatic.

Some hemoglobinopathies affect affinity for oxygen, which may be reduced or increased. If the affinity for oxygen is below its physiological value, hemoglobin oxygenation in the alveoles is limited. Blood levels of deoxygenated hemoglobin increase and give rise to cyanosis. Hb Mobile and Hb Vancouver are examples for this type of hemoglobinopathy.

An augmented affinity for oxygen usually results from mutations affecting protein segments of α- and β-chains that are in contact with each other, the binding site of 2,3-bisphosphoglyceric acid or the chains' C-terminus. Peripheral liberation of oxygen from hemoglobin is impaired and hypoxia may occur. The kidney reacts by stimulating erythropoiesis, which is why blood screenings of patients suffering from these kind of hemoglobinopathies reveal erythrocytosis, hemoglobinemia and increased hematokrit. Hb J-Capetown and Hb Chesapeake are examples for such hemoglobinopathies. Both types of hemoglobinopathies, those that reduce the protein's affinity for oxygen and those that increase it, are rare but should be considered as potential differential diagnosis.

Mutations in genes involved in hemoglobin synthesis may also affect the stability of the hemoglobin molecule. An instable hemoglobin denatures and forms so called Heinz inclusion bodies. These impair erythrocyte deformability and ultimately lead to hemolysis and anemia. Examples for these rare types of pathologic hemoglobins are Hb Gun Hill and Hb Köln. Of note, Heinz bodies are usually not visible in standard stainings, but are easily recognizable after supravital staining.

Hb M and the resulting methemoglobinemia shall be mentioned here as examples for hemoglobinopathies not affecting the globin chains. Patients presenting, for instance, Hb M-Kankakee or M-Saskatoon carry a triple positively charged iron ion instead of a twice positively charged iron ion in the heme complex of their hemoglobin. Hypoxia and cyanosis result from elevated levels of Hb M.


Because hemoglobinopathies are genetic diseases, direct prevention is not possible. If there's a family history of severe hemoglobinopathies, reproductive decisions may be taken accordingly.

Otherwise, people suffering from any hemoglobinopathy should avoid certain factors that trigger symptoms, such as infections, dehydration and specific drugs.


The term hemoglobinopathy does not describe a specific disease but is rather the name of a group of genetic disorders that lead to defective hemoglobin synthesis. In this context, hemoglobin synthesis may be affected in quantity or quality. This concept is the basis of the most general classification of hemoglobinopathies [1], as follows:

Of note, some gene disorders affect both quantity and quality of hemoglobin synthesis and therefore belong to both groups.

Most hemoglobinopathies are genetic disorders that affect one single gene and are inherited as an autosomal co-dominant trait. Whereas mutations may affect genes coding for the globin chains or other parts of the hemoglobin molecule, they may also occur in regulatory genes. The latter gives rise to the development of thalassemias, characterized by an insufficient production of functional hemoglobin. In contrast, sickle-cell anemia is probably the most known disease resulting from a structural hemoglobin variant, Hb S.

Although many hemoglobinopathies are asymptomatic, others are associated with severe anemia and require life-long treatment. Hb S, Hb C and also some thalassemias are examples for such severe forms of hemoglobinopathies.

The treatment of choice for severe hemoglobinopathies is a stem-cell transplantation. Blood transfusions may be indicated as well as symptomatic treatment. Prognosis strongly depends on the specific case: on the hemoglobinopathy and on the genetic background.

Patient Information

What are hemoglobinopathies?

Hemoglobin is what carries oxygen to all the cells of the body and it gets there by means of the red blood cells. There are certain genetic disorders that affect the amount of hemoglobin to be found in red blood cells and other genetic diseases that impair the synthesis of functional hemoglobin. In this case, the amount of hemoglobin is not reduced, but the hemoglobin present is not working well. All these diseases are called hemoglobinopathies.

There are many hemoglobinopathies. One of the more severe hemoglobinopathies (and therefore one of the more known diseases) results in sickle-cell anemia. Here, defective hemoglobin is produced and causes the red blood cells to take the shape of a sickle. Sickle-cells cannot move freely through blood vessels, the clog and break, what causes an anemia. This can lead to fatigue, delayed growth and pain.

What causes sickle cell anemia?

There are four globin chains in the hemoglobin molecule. One of these chains cannot be synthesized correctly when someone is suffering from sickle-cell anemia. The chain is still produced and included in the hemoglobin molecule, but it has an abnormal structure and is therefore called Hb S. Hemoglobin S is responsible for the sickle form adopted by red blood cells that gave the disease its name. Now, instead of smooth, round red blood cells pointy sickle-cells try to move through the blood stream. They accumulate and break, which leads to insufficient blood supply to the respective tissue and anemia. Tissue infarction is a possible consequence.

The gene affected by this genetic disorder is inherited from mother and father to the child, which means that everyone owns two copies of it. People who carry two defective copies suffer from more severe symptoms than those who possess at least one good copy of the gene. However, even people with one affected gene may experience some problems.

Since the probability for one person inheriting one or the other copy of the gene to his or her child is equal, a couple of two carriers (i.e., each one has got a good and a defective gene) has got a 25% chance to have a completely healthy child. The probability of having a child carrying two defective genes is also 25%. With a 50% chance, the child will inherit only one defective gene.

Is there a test for hemoglobinopathies?

Yes, newborns can be screened for hemoglobinopathies before leaving the hospital. A few drops of blood are needed for this test. Parents should consult with the local health care system for more information.

Can sickle-cell anemia symptoms be prevented?

Sickle-cell anemia may lead to so called sickle-cell crisis which may have life-threatening complications. It is known that infections, dehydration and some drugs can possibly trigger such a crisis and should therefore be strictly avoided. Regular vaccination helps preventing serious infections and antibiotic treatment may be necessary more often than in other patients.

Analgesics and other types of drugs may furthermore help to manage symptoms associated with sickle-cell anemia.



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  2. Weatherall D, Provan A. Red cell I: inherited anaemias. Lancet 2000; 355: 1169-75.
  3. Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ. 2001;79(8):704-712.
  4. Kohne E. Hemoglobinopathies: clinical manifestations, diagnosis, and treatment. Dtsch Arztebl Int. 2011 Aug;108(31-32):532-40. 
  5. Herklotz R, Risch L, Huber AR. [Hemoglobinopathies--clinical symptoms and diagnosis of thalassemia and abnormal hemoglobins]. Ther Umsch. 2006 Jan;63(1):35-46.
  6. Kutlar F. Diagnostic approach to hemoglobinopathies. Hemoglobin. 2007;31(2):243-50.
  7. Cario H, Stahnke K, Sander S, Kohne E. Epidemiological situation and treatment of patients with thalassemia major in Germany: results of the German multicenter beta-thalassemia study. Ann Hematol. 2000 Jan; 79(1):7-12.
  8. Steinberg MH. Sickle cell anemia, the first molecular disease: overview of molecular etiology, pathophysiology, and therapeutic approaches. ScientificWorldJournal. 2008 Dec 25; 8():1295-324.
  9. Dickerhoff R, von Rücker A, Maschmeyer G, Heimpel H. [Problems of adult sickle cell patients in Germany]. Dtsch Med Wochenschr. 2009 May; 134(22):1179-84.
  10. Gattermann N. The treatment of secondary hemochromatosis. Dtsch Arztebl Int. 2009 Jul; 106(30):499-504, I.

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Last updated: 2018-06-22 08:00