Physiology, Fetal Hemoglobin


Article Author:
Daniel Kaufman


Article Editor:
Sarah Lappin


Editors In Chief:
Chaddie Doerr


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
4/16/2019 11:17:52 PM

Introduction

Fetal hemoglobin (HbF) is produced by erythroid precursor cells from 10 to 12 weeks of pregnancy through the first 6 months of postnatal life. The genes that express gamma chain proteins are found in the beta chain locus on chromosome 11. It contains two alpha and two gamma subunits while the major form of adult hemoglobin, HbA, contains two alpha and two beta subunits. The gamma subunit differs from its adult counterpart in that it contains either an alanine or a glycine at position 136, both of which are neutral, nonpolar amino acids. This introduces conformational changes to the protein that gives rise to several physiological differences in oxygen delivery that are important in the fetal circulation.[1][2][3]

Cellular

The lower oxygen tension in the fetus is important for development, particularly angiogenesis. The course of growing blood vessels is motivated in large part through the delivery to tissues expressing the transcription factor hypoxia-inducible factor 1 (HIF1). Fetal hemoglobin’s oxygen dissociation curve is left-shifted compared to HbA. The P50 for fetal hemoglobin is 19mm Hg, compared to 27 for HbA. This indicates a higher affinity for oxygen, giving HbF the ability to “pull and hold onto” oxygen from the maternal circulation. Two other physiologic conditions make HbF effective at this. Firstly, HbF also shows a decreased affinity for 2,3DPG, a metabolic intermediate produced in tissues under heavy energy use (low ATP, high acid production). 2,3DPG introduces a right shift in HbA, favoring unloading of oxygen, but does not readily bind to HbF. 2,3DPG is essential for proper oxygen unloading in the postnatal circulation. Secondly, the fetal hematocrit (15g/dL) is higher than that in the mother (12g/dL), yielding a higher potential oxygen content per liter of blood. These both maintain the required low oxygen tension in the growing infant and contribute further to the higher affinity required to pull oxygen from HbA in the placenta. In the fetal systemic circulation, the low oxygen tension allows proper unloading of oxygen, despite HbF's affinity. [4][5][6]

Development

HbF is preceded by the embryonic hemoglobins, whose production in the yolk sac (weeks 3 through 8) decreases shortly after HbF is produced in the liver (weeks 6 through 30), followed by the spleen (9 through 28), and finally bone marrow (28 through birth). By one year of age, HbF proportion has decreased to just 1% to 2%, the level found in adults. The switch from gamma to beta chain occurs through a transcriptional switch in erythroid precursor cells in the bone marrow.

Related Testing

Measurement of fetal hemoglobin is also used in the evaluation of pregnancy conditions. The Apt (alkali denaturation) test is used on blood found in neonatal stool or vomit. It makes use of HbF's resistance to oxidation. In short, samples are lysed, centrifuged (giving a pink solution), and exposed to sodium hydroxide. HbA will bind hydroxide to form hematin, turning the sample brown, but HbF-containing solutions will remain pink. In the former case, the presence of HbA indicates maternal hemorrhage, likely a laceration, whereas HbF indicates vasa previa or another placental bleed. The Kleihauer-Betke test is used to assess the extent of maternal-fetal hemorrhage and the required dose of RhoD Ig for Rh-negative moms, for prevention of Rh antibodies against future infections. The test utilizes HbF's resistance to acid. A blood smear taken from the mother is exposed to an acid bath, which leaves HbF cells red while maternal cells appear white or "ghost-like." Calculate the appropriate dose based on the percentage of red to white cells, accounting for the estimated fetal weight and blood volume.

Pathophysiology

In alpha thalassemia, one or more of the four alpha-chain genes are deleted on chromosome 16, leading to decreased production and abnormal hemoglobins made from beta chains or gamma chains. The severity is dependent upon the number (1 to 4) of deleted genes. Deletion of a single gene is largely asymptomatic, while deletion of three genes presents with chronic microcytic anemia and symptomatic hemolysis (fatigue, hepatosplenomegaly, pigmented gallstones). With all four genes deleted, an abnormal hemoglobin composed of four gamma chains is seen, termed Hb Barts (four gamma chains). Hb Barts is incompatible with life because the gamma chains have too great an affinity for oxygen and therefore delivery is significantly impacted. Affected fetuses suffer from hydrops fetalis, marked by accumulations of fluid throughout the body such as ascites, pleural effusions, pericardial effusions, and scalp edema. The result is spontaneous abortion in nearly all cases. [7][8][9]

Clinical Significance

One medical application of the properties of HbF is in the management of sickle cell anemia. Through an unknown mechanism, hydroxyurea increases the fraction of fetal hemoglobin found in adults. At baseline, HbF accounts for 2% to 20% of hemoglobins in sickle cell disease, depending on various patient-dependent factors, and this elevation is thought to be due to the greater oxygen affinity. Due to the greater affinity, HbF is less likely to deoxygenate, sickle, and cause pain crises in these patients. Indeed, sickle cell disease patients do not manifest symptoms in infancy due to elevated HbF. HbA shows a decreased half-life in sickle cell because vaso-occlusive crises that occur during sickling/deoxygenation induce hemolysis. The proportion of HbF in the hydroxyurea-treated sickle cell is further increased, but this level is also variable from patient-to-patient and can be as high as 30% to 40%.  [10]

Measurement of fetal hemoglobin also is used in evaluating pregnancy conditions.  The Apt test is used on blood found in neonatal stool or vomit. It makes use of HbF's resistance to oxidation. In short, samples are lysed, centrifuged (giving a pink solution), and exposed to sodium hydroxide. HbA will bind hydroxide to form hematin, turning the sample brown, but HbF-containing solutions will remain pink. In the former case, the presence of HbA indicates maternal hemorrhage, likely a laceration, whereas HbF indicates vasa previa or another placental bleed. The Kleihauer-Betke test is used to assess the extent of maternal-fetal hemorrhage and the required dose of RhoD Ig for Rh negative moms, for prevention of Rh antibodies against future infections. The test utilizes HbF's resistance to acid. A blood smear taken from the mother is exposed to an acid bath, which leaves HbF cells red while maternal cells appear white or "ghost-like." Calculations based on the percentage of red: white cells, accounting for estimated fetal weight and blood volume, yield the appropriate dose. 


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Physiology, Fetal Hemoglobin - Questions

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A newly pregnant couple comes to see you in the clinic. The mother is a biochemist and has questions about oxygen transport in her growing fetus compared to transport in her and her husband's blood. Which of the following components do the parents' and fetus' hemoglobins share?



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Analysis of a blood sample obtained from the umbilical cord of a newborn infant is reported as containing 75% of its hemoglobin as hemoglobin F. Which of the following is true?



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Fetal hemoglobin is demonstrated by:



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Physiology, Fetal Hemoglobin - References

References

Fossen Johnson S, Methemoglobinemia: Infants at risk. Current problems in pediatric and adolescent health care. 2019 Apr 4;     [PubMed]
Ansari SH,Lassi ZS,Khowaja SM,Adil SO,Shamsi TS, Hydroxyurea (hydroxycarbamide) for transfusion-dependent β-thalassaemia. The Cochrane database of systematic reviews. 2019 Mar 16;     [PubMed]
Janbek J,Sarki M,Specht IO,Heitmann BL, A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment. European journal of clinical nutrition. 2019 Feb 19;     [PubMed]
Piccin A,Murphy C,Eakins E,Rondinelli MB,Daves M,Vecchiato C,Wolf D,Mc Mahon C,Smith OP, Insight into the complex pathophysiology of sickle cell anaemia and possible treatment. European journal of haematology. 2019 Apr;     [PubMed]
Wienert B,Martyn GE,Funnell APW,Quinlan KGR,Crossley M, Wake-up Sleepy Gene: Reactivating Fetal Globin for β-Hemoglobinopathies. Trends in genetics : TIG. 2018 Dec;     [PubMed]
Zivot A,Lipton JM,Narla A,Blanc L, Erythropoiesis: insights into pathophysiology and treatments in 2017. Molecular medicine (Cambridge, Mass.). 2018 Mar 23;     [PubMed]
Ghiaccio V,Chappell M,Rivella S,Breda L, Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges. Molecular diagnosis     [PubMed]
Esrick EB,Bauer DE, Genetic therapies for sickle cell disease. Seminars in hematology. 2018 Apr;     [PubMed]
Asadov C,Alimirzoeva Z,Mammadova T,Aliyeva G,Gafarova S,Mammadov J, β-Thalassemia intermedia: a comprehensive overview and novel approaches. International journal of hematology. 2018 Jul;     [PubMed]
Zaidi AU,Heeney MM, A Scientific Renaissance: Novel Drugs in Sickle Cell Disease. Pediatric clinics of North America. 2018 Jun;     [PubMed]

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