Hemoglobinopathy
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Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Most common hemoglobinopathies include sickle-cell disease and thalassemia.
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[edit] Symptoms
Most clinically significant hemoglobinopathies cause mild to acute anemia, in rare cases hemolytic anemia. Symptoms vary for the different diseases: in sickle cell disease the red blood cells tend to assume a different shape under anaerobic conditions, leading to organ damage and circulatory problems, while in thalassemia there is ineffective production of red blood cells (erythropoiesis).
[edit] Diagnosis
Diagnosis of hemoglobinopathies relies on identification and often quantitation of hemoglobin variants. Identification is aided by patient history and clinical presentation due to the genetic etiology of hemoglobinopathies. Screening and identification of most hemoglobin variants relies on High performance liquid chromatography (HPLC) and electrophoresis. Some cases are confirmed and differentiated with isoelectro focusing, globin chain electrophoresis, hemoglobin stability tests and ultimately DNA sequencing.
[edit] Electrophoresis
In alkaline (pH 8.6) and acid (pH 6.2) electophoresis red blood cell lysate is put into cellulose acetate or agar support medium and placed in an electric field. Each hemoglobin band has a characteristic migration sequence based on the size and charge of the hemoglobin-agaropectin complex. Migration generally goes from the anode (-) to the cathode (+). These methods reliably separate Hemoglobin A (alpha2-beta2) from Hemoglobin S (alpha2-betaS2), Hemoglobin C (alpha2-betaC2), and others.
[edit] Globin chain electrophoresis
Globin chain electrophoreis is a method in which hemoglobin lysate is mixed with hydrochloric acid and acetone, the heme group is removed by repeated washing of the precipitated globin by acetone. The globin chains are dissociated into monomers by urea and then separated on the basis of charge differences by electophoresis at both acid (pH 6.2) and alkaline (pH 8.9) environments. This method is used as an extension to HPLC when both alpha chain variants and beta chain variants are present within the same individual (dual heterozygote). An example would be a patient with dual Hgb G Philadelphia (alpha chain variant) and Hgb C (beta chain variant).
[edit] Isoelectric focusing
Isoelectric focusing is an electrophoretic method which utilizes carrier ampholytes (small proteins which carry both charge and pH). These compounds have molecular weights of 300-1000 Daltons. The ampholytes are incorporated into the support medium (agar) and they establish a pH gradient when charged. High voltages are used to separate the ampholytes due to large concentrations within the medium. Each hemoglobin will travel until its isoelectric point (zero charge) where migration stops. Isoelectric focusing gives better resolution than alkaline and acid electrophoresis and produce sharper bands. The resolution, however, does have a downside in that minor glycosylated hemoglobins and aging hemoglobins (methemoglobin, glycerated hemoglobin) may cause confusion.
[edit] Migration patterns
[edit] Migration patterns (Alkaline Electrophoresis)
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.
[edit] Migration patterns (Acid Electrophoresis)
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 Hgb 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.
[edit] Common variants
- Hb S
- Hb C
- Hb E
- Hb D-Punjab
- Hb O-Arab
- Hb G-Philadelphia
- Hb Hasharon
- Hb Korle-Bu
- Hb Lepore
- Hb M
[edit] Hemoglobinopathy and evolution
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.
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| Hematological malignancy and White blood cells |
| Lymphoid: Lymphocytic leukemia (ALL, CLL, HCL) | Lymphoma (Hodgkin's disease, NHL) | LPD | Myeloma (Multiple myeloma, Extramedullary plasmacytoma) |
| Myeloid: Myelogenous leukemia (AML, CML) | MPD (Essential thrombocytosis, Polycythemia) | MDS | Myelofibrosis | Neutropenia |
| Red blood cells |
| Anemia | Hemochromatosis | Sickle-cell disease | Thalassemia | Hemolysis | Aplastic anemia | G6PD Deficiency | Hereditary spherocytosis | Hereditary elliptocytosis | Other hemoglobinopathies |
| Coagulation and Platelets |
| Thrombosis | Deep vein thrombosis | Pulmonary embolism | Hemophilia | ITP | TTP | DIC |
