Hemoglobin Abnormalities

Order a hemoglobin test to evaluate your hemoglobin levels, a protein in your red blood cells that carries oxygen from your lungs to the rest of your body. If your hemoglobin levels are abnormal, it may be a sign that you have a blood disorder. Learn about your health today and order your test from Ulta Lab Tests.

Below the list of tests is a guide that explains and answers your questions on what you need to know about hemoglobin tests, along with information on hemoglobin abnormalities, signs, symptoms, and diagnosis.


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The detection and proper identification of hemoglobinopathies and thalassemias is an important aspect of the evaluation of patients with anemia, microcytosis and erythrocytosis.

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Screening test to determine presence of sickling hemoglobins, e.g., Hemoglobin S; Hemoglobin C, Harlem; Hemoglobin Georgetown.

A Complete Blood Count (CBC) Panel is used as a screening test for various disease states including anemia, leukemia, and inflammatory processes.

A CBC blood test includes the following biomarkers: WBC, RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW, Platelet count, Neutrophils, Lymphs, Monocytes, Eos, Basos, Neutrophils (Absolute), Lymphs (Absolute), Monocytes(Absolute), Eos (Absolute), Basos (Absolute), Immature Granulocytes, Immature Grans (Abs)

NOTE: Only measurable biomarkers will be reported.

Reflex Parameters for Manual Slide Review
  Less than  Greater Than 
WBC  1.5 x 10^3  30.0 x 10^3 
Hemoglobin  7.0 g/dL  19.0 g/dL 
Hematocrit  None  75%
Platelet  100 x 10^3  800 x 10^3 
MCV  70 fL  115 fL 
MCH  22 pg  37 pg 
MCHC  29 g/dL  36.5 g/dL 
RBC  None  8.00 x 10^6 
RDW  None  21.5
Relative Neutrophil %  1% or ABNC <500  None 
Relative Lymphocyte %  1% 70%
Relative Monocyte %  None  25%
Eosinophil  None  35%
Basophil  None  3.50%
     
Platelet  <75 with no flags,
>100 and <130 with platelet clump flag present,
>1000 
Instrument Flags Variant lymphs, blasts,
immature neutrophils,  nRBC’s, abnormal platelets,
giant platelets, potential interference
     
The automated differential averages 6000+ cells. If none of the above parameters are met, the results are released without manual review.
CBC Reflex Pathway

Step 1 - The slide review is performed by qualified Laboratory staff and includes:

  • Confirmation of differential percentages
  • WBC and platelet estimates, when needed
  • Full review of RBC morphology
  • Comments for toxic changes, RBC inclusions, abnormal lymphs, and other
  • significant findings
  • If the differential percentages agree with the automated counts and no abnormal cells are seen, the automated differential is reported with appropriate comments

Step 2 - The slide review is performed by qualified Laboratory staff and includes: If any of the following are seen on the slide review, Laboratory staff will perform a manual differential:

  • Immature, abnormal, or toxic cells
  • nRBC’s
  • Disagreement with automated differential
  • Atypical/abnormal RBC morphology
  • Any RBC inclusions

Step 3 If any of the following are seen on the manual differential, a Pathologist will review the slide:

  • WBC<1,500 with abnormal cells noted
  • Blasts/immature cells, hairy cell lymphs, or megakaryocytes
  • New abnormal lymphocytes or monocytes
  • Variant or atypical lymphs >15%
  • Blood parasites
  • RBC morphology with 3+ spherocytes, RBC inclusions, suspect Hgb-C,
  • crystals, Pappenheimer bodies or bizarre morphology
  • nRBC’s

Before ordering this test consider The Complete Blood Count (CBC) with Differential and Platelets Blood Test (Test # 6399) which is a better value.

In Quest's internal studies of more than two thousand patient samples, no significant abnormalities were detected with manual differentials associated with test code 20253 that were not otherwise identified thru the test code 6399 CBC Reflex cascade.

This test is a CBC reflex test and it will include the components of the CBC (Includes Diff/PLT) with Smear Review based upon the test results of the following analytes if are above or below ranges as outlined in the test.

 
 
  • WBC 
  • Hemoglobin 
  • Hematocrit 
  • Platelet 
  • MCV 
  • MCH 
  • MCHC 
  • RBC 
  • RDW 
  • Relative Neutrophil % 
  • Relative Lymphocyte % 
  • Relative Monocyte % 
  • Eosinophil 
  • Basophil 
  • Platelet 

Usual method for determining anemia. Used to calculate indices.

Unstable hemoglobins result from mutations around the heme pocket as well as contact points between the individual globin subunits resulting in hemolytic anemia. Hemoglobins carrying these structural modifications may denature and precipitate when exposed to alcohol, such as isopropanol.

Usual method for determining anemia. Used to calculate indices.

Serum iron quantification is useful in confirming the diagnosis of iron-deficiency anemia or hemochromatosis. The measurement of total iron binding in the same specimen may facilitate the clinician''s ability to distinguish between low serum iron levels caused by iron deficiency from those related to inflammatory neoplastic disorders. The assay for iron measures the amount of iron which is bound to transferrin. The total iron binding capacity (TIBC) measures the amount of iron that would appear in blood if all the transferrin were saturated with iron. It is an indirect measurement of transferri

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Transferrin is a direct measure of the iron binding capacity. Transferrin is thus useful in assessing iron balance. Iron deficiency and overload are often evaluated with complementary laboratory tests.

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Useful in the diagnosis of hypochromic, microcytic anemias. Decreased in iron deficiency anemia and increased in iron overload.


Ferritin, Iron and TIBC Panel contains: Ferritin, Iron and Total Iron Binding Capacity (TIBC)


Includes

  • Hemoglobin A, Hemoglobin F, Hemoglobin A2 (Quant), Hemoglobin A2 Prime, Hemoglobin S, Hemoglobin C, Hemoglobin D, Hemoglobin G, Hemoglobin Lepore, Hemoglobin E, Hemoglobin Barts, Variant Hemoglobin, HPLC, Hemogram (Red Blood Cell Count, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW), Ferritin and Interpretation
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  • This is a reflexive profile. Additional testing, such as molecular tests, will be added at an additional charge, if indicated.
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  • If results suggest sickling hemoglobin, Sickle Cell Screen will be performed at an additional charge (CPT code(s): 85660). 
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  • If results suggest an unstable hemoglobin based on % of the variant and pattern seen on HPLC and Electrophoresis , Unstable Hemoglobin (Isopropanol) will be performed at an additional charge (CPT code(s): 83068).
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  • If the hemogram shows microcytosis or decreased MCH or both and, there is no evidence of beta thalassemia (i.e., normal A2 and HbF), Alpha Globin common mutation analysis will be performed at an additional charge (CPT code(s): 81257). In consultation with the client, this test may also be performed (at an additional charge) in an individual with a normal hemogram for genetic counseling purposes as individuals with mild alpha thalassemia commonly have a normal hemogram and normal fractions.
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  • If HPLC or CZE, point to an unidentified alpha globin variant, the sample will be sent for DNA sequencing and Alpha Globin Complete will be performed at an additional charge (CPT code(s): 81259).
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  • If the genotyping results for the common deletions do not match the phenotype, Alpha Globin Gene Deletion or Duplication will be performed at an additional charge (CPT code(s): 81269) and Alpha Globin Complete will be performed at an additional charge (CPT code(s): 81259).
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  • If a rare beta globin variant cannot be definitively identified by HPLC or CZE, Beta Globin Complete will be performed at an additional charge (CPT code(s): 81364).
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  • If result suggests Hereditary persistence of fetal hemoglobin or Delta beta thalassemia or a beta thalassemia with negative beta globin sequencing, Beta globin gene dosage assay will be performed at an additional charge (CPT code(s) 81363).
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  • Gamma globin gene sequencing or delta globin gene sequencing may be added at an additional charge, if clinically indicated. These tests are performed at an outside reference lab. Not applicable to CA and FL clients.
  • If a reflex test is added, Genotype/phenotype review will be added at an additional charge (CPT code(s) 80500).

 

Clinical Significance

Thalassemia and Hemoglobinopathy Comprehensive Evaluation - Thalassemia and hemoglobinopathies are disorders related to hemoglobin pathophysiology. Although hemoglobinopathies and thalassemias are two genetically distinct disease groups, the clinical manifestations of both include anemia of variable severity and variable pathophysiology.
Thalassemias are group of autosomal recessive disorder of hemoglobin synthesis characterized by the reduction in the rate of synthesis of globin chain of one or more globin chain. The decreased synthesis of globin chain may result from gene deletion, non-sense mutation or mutation that affects the transcription or stability of mRNA products. Thalassemias are classified by the type and magnitude of decreased synthesis of the globin chain and severity of the clinical symptoms. The clinical manifestation ranges from mild anemia with microcytosis to fatal severe anemia.
In the alpha-thalassemias, there is absence or decreased production of beta-globin subunits, whereas in the beta- thalassemias, there is absent or reduced production of beta globin subunits. Rare thalassemias affecting the production of delta or gamma globin subunits have also been described but are not clinically significant disorders.
The beta-thalassemias can be sub-classified into those in which there is total absence of normal beta globin subunit synthesis or accumulation, the beta-zero thalassemias, and those in which some structurally normal beta globin subunits are synthesized, but in markedly decreased amounts, the beta-plus thalassemias. The alpha-thalassemia syndromes however, are usually caused by the deletion of one or more alpha globin genes and are sub-classified according to the number of alpha globin genes that are deleted (or mutated): one gene deleted (alpha-plus thalassemia); two genes deleted on the same chromosome or in cis (alpha-zero thalassemia); three genes deleted (HbH disease); or four genes deleted (hydrops fetalis with Hb Bart's).
Hemoglobinopathies results from the abnormal structure of One of the globin chains of the hemoglobin molecule (mutation of alpha and/or beta globin chain resulting in a variant form of Hemoglobin A). They are inherited single- gene disorders and in most cases, they are inherited as autosomal co-dominant traits. A large number (>800) of variants of hemoglobin (Hb) have been recognized. They are identified by capital letters (eg, Hb A or Hb S), or by the city in which the variant was first discovered (eg, Hb Koln).
Alpha chain variants usually form less than 25% of the total hemoglobin because the mutation typically occurs in one of the four genes that codes for alpha globin chain. For beta globin variants in the heterozygous state the variant forms more than 25% but less than 50% of the total hemoglobin. Ranked in order of relative frequency, these are: Hb S (sickle cell disease and trait), C, E, Lepore, G-Philadelphia, D-Los Angeles, Koln, Constant Spring, O-Arab, and others.
Most common beta globin variants include HbS, HbC, HbD, HbE and HbG. A mutation in one beta globin subunit results in a combination of variant and normal hemoglobin and denotes carrier or trait status, also known as the heterozygote state. Mutations in both beta globin subunits result in disease based on a homozygous expression such as sickle cell anemia (HbSS). Other diseases under sickle cell disease (SCD) are HbSE, HbSC and HbS beta-thalassemia.



Hemoglobin abnormalities are variant forms of hemoglobin that are frequently inherited and can cause hemoglobinopathy (a blood disorder). 

Hemoglobin is a protein compound that contains iron and is found inside red blood cells. It transports oxygen throughout the entire body. It is comprised of globin chains, which are the proteins and heme, which is the part that contains iron.

There are several different kinds of globin chains: gamma, delta, and alpha. Regular types of hemoglobin include the following:  

Hemoglobin F (fetal hemoglobin or Hb F): Around 1% to 2% of hemoglobin that is found in adults. It has two gamma protein chains and two alpha protein chains. This is the main hemoglobin that a fetus produces during pregnancy. Usually, its product drops right after birth, and within 1-2 years reaches the adult level.  

Hemoglobin A2 (Hb A2): Around 2-3% of the hemoglobin that is found in adults. It contains two delta and two alpha protein chains. 

Hemoglobin A (Hb A): Around 95% to 98% of hemoglobin that is found in adults. Hemoglobin A contains two beta and two alpha protein chains.  

Mutations (genetic changes) within the globin genes result in globin protein alterations, which result in structurally altered hemoglobin, like hemoglobin S, which can cause thalassemia (reduction in global chain production) or sickle cell. With thalassemia, when the production of a globin chain is reduced, it upsets the balance of the beta and alpha chains and causes the formation of abnormal hemoglobin (alpha-thalassemia), or it can cause an increase in minor components of hemoglobin, such as Hb F (beta-thalassemia) or Hb A2.  

There are two genes each that code for gamma, delta, and beta globin chains and four that code for alpha globin chains. Mutations can occur in either the beta or alpha globin genes. The alpha thalassemia is the most common type of alpha-chain-related condition. The severity of the condition will depend on how many genes have been affected.  

Beta gene mutations are mainly inherited in an autosomal recessive manner. That means the individual must have two copies of altered genes, one from each of their parents, to have a hemoglobin variant disease. If one abnormal beta gene and one normal beta gene are inherited, the individual is heterozygous for abnormal hemoglobin, which is referred to as a carrier. The person’s abnormal gene may be passed onto children. However, it usually does not cause the carrier any significant health concerns or symptoms.  

If two of the same type of abnormal beta genes are inherited, then the individual is homozygous. The associated hemoglobin variant will be produced by the person, and they might potentially have some associated symptoms and complications. How severe the condition is will depend on the specific genetic mutation and will vary from one individual to the next. A copy of their abnormal beta gene is passed onto any children.  

If a person inherits two different types of abnormal beta genes, then the individual is “compound heterozygous” or “doubly heterozygous.” The affected individual typically will have symptoms that are related to both or one of the hemoglobin variants that the person produces. One abnormal beta gene will pass onto any children.  

Red blood cells that contain abnormal hemoglobin might not efficiently carry oxygen and might be broken down soon by the body than normal (shortened survival), which results in hemolytic anemia. There have been several hundred variants of hemoglobin documented. However, just a few of them are clinically significant and common. Some of the more common variants of hemoglobin include hemoglobin E, which can cause generally mild or no symptoms; hemoglobin C, which might cause minor hemolytic anemia; and hemoglobin S, which is the main hemoglobin in individuals who have sickle cell disease that can cause red blood cells to turn misshapen (sickle), which reduces the cells’ survival.  

Common Hemoglobin Variants 

There have been several hundred different hemoglobin variants (abnormal forms) that have been identified. However, just a few of them are clinically significant and common.  

E: this is one of the world’s most common types of beta chain hemoglobin variants. In Southeast Asia, it is especially prevalent, particularly in Thailand, Laos, and Cambodia, and in people of Southeast Asian descent. In individuals homozygous for Hb E (have two beta chain copies), usually have a mildly enlarged spleen, microcytic red blood cells, and mild hemolytic anemia. One hemoglobin E gene copy will not cause any symptoms unless another mutation combines with it, like the beta-thalassemia trait one.  

C: Around 2-3% of U.S. African Americans are heterozygous for hemoglobin C (one copy called hemoglobin C trait). They are frequently asymptomatic. The hemoglobin C disease (those with two copies, seen in homozygotes) is relatively mild and rare (0.02% of U.S. African Americans). Usually, it causes a mild or moderately enlarged spleen and minor hemolytic anemia.  

S: this is the main hemoglobin in individuals who have sickle cell disease (which is also referred to as sickle cell anemia). The Centers for Disease Control and Prevention reports that an estimated 1 in 375 African American infants are born with sickle cell anemia, and around 100,000 Americas have this disorder. People who have Hb S disease possess two normal alpha chains and two abnormal beta chains. Hb S causes red blood cells to become deformed and turn into the sickle shape when they are exposed to reduced amounts of oxygen (like what may occur when someone has a lung infection or exercises). Sickle red blood cells are very rigid and may result in small blood vessels becoming blocked, which decreases oxygen delivery, impair circulation, cause pain, and shorten the survival of red blood cells. One beta copy (called the sickle cell trait and present in an estimated 8% of African Americans) usually doesn’t cause any serious symptoms unless another hemoglobin mutation combines with it, like that which causes beta-thalassemia or Hb C. 

Less Common Variants   

Many other variants exist. Some of them are silent and cause no symptoms or signs. Then others might affect the stability and/or functionality of the hemoglobin molecules. Other variants include Hb M, Hb J, Hb G, Hb D, and Hb Constant Spring, which is caused by a mutation within the alpha globin gene that causes an unstable hemoglobin molecule and abnormally long alpha chain.

Other examples include the following:  

F: Hb F is the main hemoglobin that the fetus produces. Its role is to efficiently transport oxygen within a low oxygen environment. Hb F production is sharply reduced after birth and by 1-2 years old reaches adult levels. In several different congenital disorders, Hb F might be elevated. In beta-thalassemia, levels can be significantly increased or normal, and in sickle cell beta-thalassemia or people with sickle cell anemia, levels are frequently increased. People with increased Hb F and sickle cell disease frequently have a milder form of the disease, since the sickling of red cells is inhibited by the F hemoglobin. Hb F levels also are increased in the hereditary persistence of fetal hemoglobin (HPFH), which is a rare condition. In these inherited disorders, there are increased Hb F levels without the clinical features or signs of thalassemia. Various ethnic groups have various mutations that may cause HPFH. Also, Hb F may be increased as well in certain acquired conditions that involved the impaired production of red blood cells. Some leukemias, as well as other types of myeloproliferative neoplasms, also are associated with mild increases in Hb F.  

H: The abnormal hemoglobin Hb H occurs in some alpha thalassemia cases. It is comprised of four beta globin chains. It is produced due to a serious shortage in alpha chains. The beta globin chains are all normal. However, on 4 of the beta chains, the tetramer does not function properly. Its affinity for oxygen is increased and holds onto it rather than releasing it to the cells and tissues. Hemoglobin H also is associated with hemolysis (serious breakdown in red blood cells) since it is very unstable and tends to form solid structures inside the red blood cells. Individuals who have hemoglobin H disease often have anemia but do not usually have serious medical problems.  

Barts: This develops in fetuses that have alpha thalassemia. Hb Barts is formed from four gamma protein chains whenever there are not enough alpha chains, in a way that is like Hemoglobin H formation. If small Hb Bart levels are detected, normally it disappears soon after birth because gamma chain production dwindles. These children are silent carriers with one or two deletions of alpha genes or possess the alpha thalassemia trait. A child with large Hb Barts levels usually will have a three-gene deletion and hemoglobin H disease. Fetuses that have four-gene deletions will have hydrops fetalis and normally will not survive without bone marrow transplants and blood transfusions.   

Two separate abnormal genes can also be inherited by a person, one from each of their parents. It is referred to as being doubly heterozygous or compound heterozygous. Below are listed several different combinations that are clinically significant. 

SC disease: inheriting one beta C gene and one beta S gene causes Hemoglobin SC disease. These people have moderately enlarged spleens and mild hemolytic anemia. Individuals with Hb SC disease might develop the same blood vessel-blocking (vaso-occlusive) complications that are found in sickle cell anemia. However, most cases are not as serious.  

D disease Sickle Cell: People with sickle cell or Hb D disease inherit one copy of hemoglobin D and one hemoglobin S. Those individuals might have moderate hemolytic anemia and occasional sickle crises.  

E-beta thalassemia: People who are doubly heterozygous for beta thalassemia and hemoglobin E have anemia that may vary in severity, ranging from mild (asymptomatic) up to severe, depending on what beta thalassemia mutation(s) are present.  

S-beta thalassemia: Beta thalassemia – sickle cell various in severity, which depends on the inherited beta thalassemia mutation. Some mutations can result in the reduced production of beta globin (beta ), where it is eliminated (beto0) by others. Sickle cell beta thalassemia tends to be less severe compared to beta0 thalassemia. Individuals with sickle cell – beta thalassemia tend to have an increased number of irreversibly sickled cells, more serious anemia, and more frequent vaso-occlusive issues compared to people who have sickle cell – beta thalassemia. Often it is hard to distinguish between sickle cell – beta thalassemia and sickle cell disease.  

Symptoms and Signs  

Symptoms and signs that are associated with hemoglobin variations vary in severity and type depending on which variant is present and whether the person has a combination or one variant. Some are due to an increase in hemolysis (breakdown) of red blood cells as well as shortened red blood cell survival, which results in anemia.

The following are some examples:  

  • Pale skin (pallor) 
  • Jaundice 
  • Lack of energy 
  • Weakness, fatigue 
  • Some serious symptoms and signs include:  
  • Upper abdomen pain (caused by the formation of stones in the gallbladder) 
  • Growth problems for children 
  • Enlarged spleen 
  • Shortness of breath  
  • Severe pain episodes  

Laboratory Tests 

Hemoglobin variant lab tests explore the “normalness” of a person’s red blood cells, analyze relevant gene mutations, and/or evaluate the hemoglobin with the red blood cells. Each test offers a piece of the overall puzzle to provide important information to the clinician about whatever hemoglobin might be present.

Typically testing includes:  

Complete blood count (CBC): This test provides a snapshot of the cells that are circulating within the blood. The CBC, among other things, will let the doctor know the number of red blood cells that are present, the amount of hemoglobin inside of them, and provide an evaluation to the doctor of red blood cells’ average size.  

Mean corpuscular volume (MCV) measures the red blood cells’ size. Low MCV frequent is an early indication of thalassemia. If there is low MCV and iron-deficiency is ruled out, then the person might have a hemoglobin variant that is the result of red blood cells that are smaller than normal (Hb E, for example) or be a thalassemia trait carrier.  

Blood smear (or peripheral smear): A trained laboratorian will look under a microscope at a thin blood layer on a slide that has been treated using a special stain. The type and number of platelets, red blood cells, and white blood cells can be evaluated in order to determine whether they are mature and normal.

With hemoglobinopathy, red blood cells might be:  

  • Microcytic (smaller than normal) 
  • Hypochromic (paler than normal)  
  • Vary in shape (poikilocytosis – e.g., sickle-shaped cells) and size (anisocytosis) 
  • Have a crystal (e.g., C crystal) or nucleus (nucleated red blood cell, which in mature red blood cells is not normal) 
  • Uneven distribution of hemoglobin (“target cells” are produced that under a microscope resemble a bull’s eye).  

The higher the percentage of abnormal-appearing red blood cells there are, the higher the chance that an underlying disorder is present.  

Hemoglobinopathy evaluation: This type of test identifies the type and measures the relative amount of the various kinds of hemoglobin that are present in a person’s red blood cells. Most common variants may be identified using a combination or one of the tests. The relative amount of variant hemoglobin that is detected can help with diagnosing combinations of thalassemia (compound heterozygotes) and hemoglobin variants.  

Genetic testing: This type of test is used for investigating the mutations and deletions in the beta and alpha globin-producing genes. It is possible to conduct family studies to evaluate both the carrier status as well as the kinds of mutations that are present in other members of the family. Genetic testing is not done regularly. However, it may be used to help determine carrier status and confirm thalassemia and hemoglobin variants. 

Laboratory Tests 

Conditions 

  • Pregnancy: Preconception 
  • Thalassemia 
  • Sickle Cell Anemia 
  • Anemia