Can Folic Acid Help In Getting Rid Of Hbe Dieseas

Blood film in homozygous sickle cell disease. Note the elongated (sickled) red cells. Confirmatory tests

Haemoglobin electrophoresis shows 80-99% HbS with no normal HbA. HbF may be elevated to about 15%. Parents will have features of sickle cell trait.


In at-risk groups pregnant woman should be screened early in pregnancy. If both parents of fetus are carriers offer prenatal/neonatal diagnosis. Affected babies should be given penicillin daily and be immunised against S. pneumoniae, Hinfluenzae type b, and Neisseria meningitidis.

Prenatal diagnosis

May be carried out from first trimester (chorionic villus sampling from 10 weeks gestation) or second trimester (fetal blood sampling from umbilical cord or trophoblast DNA from amniotic fluid). DNA may be analysed using restriction enzyme digestion with Mst II and Southern blotting, RFLP analysis assessing both parental and fetal DNA haplotypes, oligonucleotide probes specific for sickle globin point mutation, or PCR amplification followed by restriction enzyme digestion of amplified DNA. ARMS (amplification refractory mutation system) PCR is useful in ambiguous cases. In late pregnancy fetal blood sampling may be used to confirm diagnosis.



Lifelong prophylactic penicillin 250mg bd PO with folate replacement. Pneumovax II vaccination advisable.

Management during pregnancy and anaesthesia

Anaesthesia should be carried out by experienced anaesthetist who is aware of complications of SCA. If the patient is unwell consider transfusion to Hb of 10g/dL, but generally transfusion not necessary.

Management of crises

O Haematological Emergencies: Sickle Crisis p532.


Agents that elevate HbF levels

It has been recognised for some time that 4 HbF levels ameliorate |3 thalassaemia and sickle cell disease. HbF reduces HbS polymerisation and yg hence sickling. HbF level of >10% reduces episodes of aseptic necrosis; levels >20% HbF are associated with fewer painful crises.

Hydroxyurea—several studies have shown that baboons treated with cytosine arabinoside showed 4 HbF. Similar results obtained with hydroxyurea which has advantages over other cytotoxics e.g. low risk of secondary malignancy with prolonged use. Hydroxyurea has been evaluated in a large number of clinical trials. Effects are dose-dependent and the highest elevation of HbF is seen at myelosuppressive doses.

Erythropoietin—leads to 4 HbF but not widely used in the management of haemoglobinopathies. Evidence suggests that rHuEPO provides an additive effect when alternated with hydroxyurea. Dose required is high (1000-3000iu/kg x 3d/week) with co-administration of Fe supplements.

5-azacytidine—inhibitor of methyltransferase, enzyme responsible for methylation of newly incorporated cytosines in DNA. Preventing methylation of the g globin gene leads to 4 HbF. ^^ Risk of developing 2° malignancy.

Short chain fatty acids—butyrate analogues are potent inducers of haematopoietic differentiation. Elevated concentrations of butyrate and other fatty acids in diabetic mothers is responsible for the persistently elevated HbF in the neonates born to such mothers. Initial studies involving the use of butyrate to increase HbF levels in patients with sickle cell anaemia appeared promising but subsequent studies have been disappointing.

Bone marrow transplantation—sibling donor transplants for sickle cell disease have been carried out in a number of centres. Since the mortality from sickle cell disease has dropped over recent years from 15%—>1%, and with the advent of hydroxyurea therapy, there is a less compelling argument for BMT in sickle cell disease.

Gene therapy—potentially curative but experimental. Globin gene transfer has been attempted with variable results. Expression of exogenous gene has been at levels too low to be of benefit.

Charache, S. et al (1995) Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med, 332, 1317-1322; Platt, O.S. et al. (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med, 330, 1639-1644.

Asymptomatic carriers have one abnormal |3S gene and one normal |3 gene (with 30 million carriers worldwide).

Clinical features yg • Carriers are not anaemic and have no abnormal clinical features.

• Sickling rare unless O2 saturation falls <40%. Crises have been reported with severe hypoxia (anaesthesia, unpressurised aircraft).

• Occasional renal papillary necrosis, haematuria and inability to concentrate the urine in adults.

Laboratory features

• Hb, MCV, MCH and MCHC normal (unless also a thalassaemia trait).

• HbS level 40-55% (if <40% then also a thalassaemia trait).

• Film may be normal or show microcytes and target cells.

Carrier detection

Neither FBC nor film can be used for diagnostic purposes. Detection of the carrier state relies on haemoglobin electrophoresis (HbA ~50%; HbS ~50%).

^ Care needed during anaesthesia (avoid hypoxia).


Milder than sickle cell anaemia but resembles it. Patients have fewer and milder crises. Retinal damage (microvascular, proliferative retinopathy) 80 and blindness are major complications (30-35%). Arrange regular oph-thalmological review by specialist. Aseptic necrosis of femoral head and recurrent haematuria are common. Increased risk of splenic infarcts and abscesses.

^ Beware thrombosis and PE especially in pregnancy. Clinical

Mild anaemia (Hb 8-14g/dL) and splenomegaly common. Less haemolysis, fewer painful crises, fewer infections and less vaso-occlusive disease than SCA. Growth and development normal. Lifespan normal. ^ Pregnancy may be hazardous.


Prominent target cells with fewer NRBC than seen in SCA. Howell-Jolly and Pappenheimer bodies (hyposplenism). Occasional C crystals may be seen.


Hb electrophoresis and family studies. MCV and MCH are much lower than in HbSS.

HbSD, HbSOArab

Milder than HbSS. Both rare. Interactions of these globins with HbS results in reduced polymerisation. HbDPunjab(b121 glu7gl") and HbOArab(b121 glu7lys) cause little disease on their own although there may be mild haemolysis in the homozygote. These haemoglobins cause sickle cell disease when present with HbS.

HbSa thalassaemia

Common in Black individuals. Lessens severity of SCA by reducing the concentration of Hb in red cells.

HbSp thalassaemia

Caused by inheritance of |3S from one parent and |3 thalassaemia from the other. Sickle/|3° thalassaemia is severe since no normal |3 globin chains are produced. Sickle/|3+ thalassaemia is much milder having |3 globin in 5-15% of their Hb. Microcytosis and splenomegaly are characteristic. Family screening will confirm microcytosis and 4 HbA2 in one of the parents.


Essentially as for HbSS with prompt treatment of crises (see above).

HbC disease (|36 glu7lys)

West Africa. Patients have benign compensated haemolysis. Development is normal, splenomegaly is common. Gallstones are recognised complica-82 tion. The Hb may be mildly 5. MCV and MCH 5 and reticulocytes 4. Blood film shows prominent target cells and occasional HbC crystals. Hb electrophoresis shows mainly HbC with some HbF. HbA is absent. Red cells said to be 'stiff. Care with anaesthesia.

Asymptomatic. Hb is Film may be normal or show presence of target cells. HbC 30-40%.

HbD disease (e.g. DPunjab b121 glu 7gln)

Found in North West India, Pakistan and Iran. Film shows target cells. HbD trait (e.g. DRun]ab b121 glu7gln)

Of little consequence other than interaction with HbS. Hb and MCV Film normal or shows target cells.

HbE disease (b26 glu7lys)

South East Asia (commonest Hb variant), India, Burma and Thailand. This Hb is moderately unstable when exposed to oxidants. May produce tha-lassaemic syndrome when mRNA splice mutants. There is mild anaemia, MCV and MCH 5, reticulocytes Film shows target cells, hypochromic and microcytic red cells. There are few symptoms; underlying compensated haemolysis, mild jaundice. Liver and spleen size are normal. Treatment is not usually required.

HbE trait (b26 glu7l^s)

Asymptomatic. Indices similar to b thalassaemia trait. Hb usually

Congenital Heinz body haemolytic anaemia caused by point mutations in globin genes. Hb precipitates in red blood cells—»Heinz bodies. In normal Hb there are non-covalent bonds maintaining the Hb structure; loss of bonds leads to Hb denaturation and precipitation. Production of Heinz 84 bodies leads to less deformable red cells with reduced lifespan.

Predominantly autosomal dominant; most patients are heterozygotes. Mainly affects |3 globin chain e.g. HbHammersmith (mutation involves amino acid in contact with haem pocket); HbBristol (replacement of nonpolar by polar amino acid with distortion of protein).

Clinical features

• Well compensated haemolysis.

• Hb may be if unstable Hb has high O2 affinity.

• Haemolysis exacerbated by infection and oxidant drugs.

• Jaundice and splenomegaly are common.

• Some Hbs are unstable in vitro but show little haemolysis in vivo.


• Film shows hypochromic RBCs, polychromatic RBCs, basophilic stippling.

• Heinz bodies seen post-splenectomy.

• Reticulocytes are 4.

• Demonstrate unstable Hb using e.g. heat or isopropanol stability tests.

• Brilliant cresyl blue will stain Heinz bodies.

• Estimation of P50 may be helpful.

• DNA analysis of value in some cases.


Most cases run benign course. Treatment seldom required. Gallstones common. Recommend regular folic acid supplementation. Splenectomy of value in some patients. Avoidance of precipitants of haemolysis advised.

Arise as a result of diminished or absent production of one or more globin chains. Net result is imbalanced globin chain production. Globin chains in excess precipitate within RBCs leading to chronic haemolysis in bone marrow and peripheral blood. Occur at high frequency in parts of Africa, 86 the Mediterranean, Middle East, India and Asia. Found in high frequency in areas where malaria is endemic and thalassaemia trait probably offers some protection.

Named after affected gene e.g. in a thalassaemia the a globin gene is altered in such a way that either a globin synthesis is reduced (a+) or abolished (a°) from RBCs. Severity varies depending on type of mutation or deletion of the a or |3 globin gene.

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