Introduction
Hemoglobin is a transport protein that is present in red blood cells. Its prime function is to carry oxygen in the blood and deliver it to tissues. Any abnormality in the structure or defective production of hemoglobin affects the oxygen-carrying capacity of the Hb molecule leading to profound clinical manifestations. This article enumerates different types of abnormalities in hemoglobin and highlights the clinical aspects of those variants with increased oxygen affinity.
What Is Abnormal Hemoglobin?
Normal adult hemoglobin (HbA) is a metalloprotein that consists of four heme (iron-containing) units and four polypeptide chains (two alpha chains and two beta chains). The structure (amino acid sequence) of the polypeptide (globin) chains is very important to facilitate oxygen binding with the heme molecule. These globin chains not only favor oxygen binding in oxygenated blood but also help in the dissociation of oxygen in tissues. Changes in the structure (amino acid substitution) of polypeptide chains alter the normal functioning of hemoglobin.
Abnormal hemoglobin occurs due to changes in globin chains resulting in numerous hemoglobin variants and are termed hemoglobinopathies. The variations are genetically inherited, where the genes code for altered amino acid sequences, resulting in defective alpha or beta chains. Based on clinical manifestations, they are classified as-
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Sickle-Cell Syndromes - HbS (sickle hemoglobin).
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Unstable Hemoglobins - Hb Zurich, congenital Heinz body anemia.
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Hemoglobin With High Oxygen Affinity - Familial polycythemia, Hb Chesapeake, Hb Olympia.
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Hemoglobin With Low Oxygen Affinity - Familial cyanosis, HbM, Hb Kansas.
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Abnormal Hemoglobin Due to Defective Rate of Globin Synthesis - Thalassemias (here, the globin structure is normal, but production is abnormal).
Apart from hemoglobinopathies, there are other hemoglobin derivatives where hemoglobin expresses increased oxygen affinity, such as-
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HbF (Fetal Hemoglobin) - It is present in the fetus and the newborn and contains two gamma chains instead of beta chains. These gamma chains have more affinity for oxygen to enhance fetal growth and development.
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CO-Hb (Carboxy-hemoglobin) - It is formed during carbon monoxide poisoning, binds with more oxygen molecules, and does not release them to the tissues resulting in increased oxygen affinity.
What Are the Signs and Symptoms of Abnormal Hemoglobin With Increased Oxygen Affinity?
Abnormal Hb with high oxygen affinity is seen in globin variants like Hb Chesapeake (alpha chain variant), Hb Olympia, and familial polycythemia (both are beta chain variants). They are inherited as autosomal dominant traits, usually heterozygous (asymptomatic) but sometimes homozygous that exhibit clinical symptoms. When these variants are expressed, the hemoglobin binds with oxygen normally but has difficulty in the unloading of oxygen at the tissue level due to defective amino acid sequences. This leads to tissue hypoxia which eventually triggers erythropoiesis resulting in increased production of red blood cells (erythrocytosis). The following clinical manifestations include;
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Ruddy complexion (reddish discoloration of the skin).
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Mucosal erythema.
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Polycythemia (increased RBC count).
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Hyperviscosity symptoms like headaches, vertigo, tinnitus, and paraesthesia in extremities.
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Thrombotic complications (deep vein thrombosis, pulmonary embolism, and stroke).
What Are the Laboratory Investigations of Abnormal Hemoglobin With Increased Oxygen Affinity?
The laboratory investigations asses two variables; one is to detect increased oxygen affinity due to the Hb variants like the p50 test and oxygen dissociation curve analysis, and the other is to identify the abnormal amino acid sequence in the globin chain to categorize the variant Hb, such as Hb electrophoresis and protein sequencing.
To Detect Increased Oxygen Affinity
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Hb concentration is higher than 20 g/dL (grams per deciliter).
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Oxygen saturation curve - oxygen binding (saturation) is estimated with the help of the Clark oxygen electrode, and measurements are represented as a sigmoid oxygen affinity curve (normal HbA). The sigmoid curve shifts to the left (compared with the normal curve), indicative of more binding of oxygen than dissociation.
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p50 testing - partial pressure of oxygen (p50) is low (below 19), suggesting poor dissociation at the tissue level. This is done by arterial blood gas (ABG) analysis.
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Elevated levels of erythropoietin hormone (EPO) secretion is increased from the kidneys as the result of secondary erythropoiesis.
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Hematocrit (HCT) values are increased above the normal standard values due to the increased viscosity of the blood.
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Reduced pulse oximetry values due to cardiorespiratory symptoms.
To Identify Defective Globin Chain
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Hemoglobin separation testing.
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Hb variants with high oxygen affinity show marked separation from HbA during electrophoresis and chromatography.
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Reverse-phase high-performance liquid chromatography (HPLC) is performed to separate globin chains.
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Hemoglobin stability is determined by the isopropanol test.
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Molecular analysis by DNA sequencing of the α and β genes helps to identify the type of Hb variant. It also detects unknown variants.
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Specialized staining of β-chains in tryptic peptide maps identifies altered chains.
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Amino acid sequencing and analysis detect abnormal sequencing patterns.
What Is the Clinical Management of Abnormal Hemoglobin With Increased Oxygen Affinity?
As the diagnosis of such Hb variants is challenging due to coexisting clinical symptoms, a detailed family history with previous clinical episodes of altered oxygen affinity symptoms is highly valuable. The primary intervention includes symptomatic management.
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Intervention of Thrombogenic and Embolic Complications - Administration of antithrombotic agents as per guidelines according to the type of thrombotic symptom. The intensity and duration of anticoagulation therapy must be evaluated frequently to avoid secondary complications of polycythemia (an abnormal increase in red blood cells).
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Treatment for Hyperviscosity - Therapeutic phlebotomy (puncturing the vein to withdraw blood) of 200 to 500 mL is performed, which is monitored and regulated according to Hb and HCT values. Phlebotomy is repeated to minimize HCT values. Tolerance levels and symptoms related to reduced oxygen-carrying capacity are closely monitored.
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Asymptomatic Individuals - High suspicion index is needed in individuals with high Hb and HCT values to rule out other mimicking conditions. Precautions are to be taken in situations prior to any major surgery or general anesthesia in individuals who have increased hematocrit values.
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Low-dose Aspirin Administration: It is proven useful in polycythemia conditions to avoid thrombogenic complications like myocardial infarction, stroke, pulmonary embolism, or other morbid consequences.
Conclusion
Increased oxygen affinity Hb variant occurs due to rare genetic coding for defective globin chains. The prime step in detecting such a variant Hb is through awareness of common clinical and laboratory findings. A detailed family history of high oxygen affinity Hb is essential to raise suspicion and sequent evaluation. Gaining knowledge on the pathophysiology of the increased oxygen affinity Hb variant would assist in conducting appropriate and advanced diagnostics and optimizing management protocols.
