Group of chronic microcytic hemolytic anemias transmitted on  an autosomal recessive mode and linked to a quantitative (not qualitative) defect in synthesis of one of the chains, α or β, of the hemoglobin. The fact of being heterozygous carrier for one of these diseases appears to protect against malaria caused by Plasmodium falciparum, which explains their geographic distribution.

1) β-Thalassemias [MIM 613 985]

They result from mutations on chromosome 11, more than 100 types of which have been identified. They occur mainly in populations of mediterranean origin ("thalassa" meaning "sea" in Greek): Greece, Turkey, North Africa, Middle East, South of Italy:

hemoglobins Cagliari and Knossos are part of the β-thalassemias.  One distinguishes the β-Thalassemia β °, where there is no β chain synthesis and β+, where the synthesis is only decreased.

The lack of β chains leads to a excess of α chains that precipitate (anemia and hemolysis) and some of which may bind to δ chains to form HbF (normal level < 1% at the age of 12 months).

1. homozygous form: Cooley disease

Homozygous, and most severe, form of β-thalassemia. The diagnosis is usually made before the age of 1 year, in presence of chronic infantile anemia and a high level of hemoglobin F. 

In addition with conjunctival pallor:

-         a particular facies: hypertelorism, flattening of the base of the nose, advanced maxillary edge and of the upper lip, expansion of malar bone ('chipmunk head'); those distortions are due to erythropoietic hyperplasia of the bone of the face; those anomalies are moderate in regularly transfused children;

-         hepatosplenomegaly;

-         thrive which will worsen during growth if the management is inadequate.

X-ray of the skull often shows 'brush hair'-like striations and osteoporosis. 

Diagnosis: severe hypochromic microcytic anemia, moderate reticulocytosis, hyperbilirubinemia, increased  concentration of serum iron and ferritin. The diagnosis is confirmed by  electrophoresis of hemoglobin showing a high level of fetal Hb (HbF) (up to 100 %). 

Evolution: complications are related to chronic hypoxia and iron overload, and are therefore avoidable by the treatment of anemia  associated with the administration of the iron chelating agents:

-        hepatic insufficiency: cirrhosis due to hemochromatosis or following infection consecutive to the blood transfusions

-        endocrine perturbations: iron overload induces a pituitary dysfunction: growth retardation, hypogonadism, hypothyroidism (between the age of 10 and 20 years); diabetes mellitus during late adolescence

-        hemochromatosis following chronic transfusions but also to an increased intestinal absorption of iron 

-        heart failure secondary to hypokinetic dilated cardiomyopathy following excess of myocardial iron  (transfusions), sometimes acute myocarditis; long QT with risk of sudden death;

-        pulmonary hypertension (50-75 % of cases) because the arginase and the free hemoglobin produced by hemolysis eliminate the endogenous NO and the chronic hypoxemia increases the pulmonary resistances; moreover, the repeated transfusions and the iron overload cause an endothelial dysfunction; moreover, after splenectomy, the red blood cells remnants are not eliminated by the spleen and can occlude the pulmonary capillaries

-        secondary restrictive pulmonary syndrome caused by iron overload (fibrosis and interstitial edema)

-        blood hypercoagulability and arterial or venous thromboembolic risk (especially after splenectomy)

-        anomalies of renal tubular function following anemia, iron overload and chelation therapy: increased creatinine clearance, important urinary elimination of Ca, PO4; Mg; proteinuria

-        osteopenia and osteomalacia with significant risk of fractures (+ pain linked to microfractures)

-        a compensatory extramedullary erythropoiesis leads to overgrowth of bone which can compromise vision (optic nerves compression) and hearing; cases of narrow vertebral canal with signs of spinal compression have been reported

Life expectancy is greatly reduced: unless an effective medical treatment is followed, death occurs around an average of 5 years after the onset of symptoms of heart failure. In developed countries, the onset of cardiac symptoms is exceptional before adulthood.

Treatment: regular transfusions to maintain the Hb level above 100 g/L. Those transfusions are associated with iron chelation by desferrioxamine (IV or subcutaneous) associated to vitamin C (or deferiprone or deferasirox by mouth). 

Splenectomy is indicated before the appearance of signs of hypersplenism. Transplantation of  allogeneic bone marrow (children less than 7 years) is the only curative treatment.

2. heterozygous form of ß-thalassaemia: thalassaemia trait

Paucisymptomatic: pallor and fatigue, palpable spleen. There is a hypochromic microcytic polycythemia. The  iron blood levelis normal and there is often an anisocytosis with cells in target on the blood smear. Diagnosis is made by electrophoresis of Hb which shows an increase of Hb A2 (normal < 3.5 %).

(2) intermediate or minor thalassemias

Intermediate or minor thalassemias are a heterogeneous group of patients, at a genetic as well as clinically level and their symptomatology is intermediate between the thalassaemia trait and Cooley disease. The association α-β thalassemia attenuates the severity of each of both forms separately. The treatment is also guided by hemoglobin level

3) α-Thalassemias [MIM 604 131]

The α-thalassemias are mostly related to a deletion, more rarely a mutation at the level of chromosome 16p13.3pter. They primarily affect black and asian populations (South-East Asia). It is one of the most widespread diseases in the human species. The production of the chain α of Hb is controlled by 4 genes (HBA1 and HBA2) and there are as many forms of α-thalassemias:

The severity of the clinical presentation depends on the number of defective genes, ranging from virtually subclinical forms (1 single defective gene) to hydrops foetalis (4 defective genes). 

Hemoglobin Bart gives a hydrops foetalis (hydrops fetalis with fetal or neonatal death) and a clinical picture of pre-eclampsia or eclampsia in the mother. 

There is 10 to 40 % Hb Bart in the blood of a newborn suffering from α thalassemia (5-10% in case of minor form).  β chains produced in excess compared to α chains can precipitate in erythrocytes as Heinz bodies.

The 3 defective genes form corresponds to hemoglobin H. Hemoglobin H is unstable and its affinity for O2 is increased: this produces chronic tissue hypoxia whose importance varies according to the type of mutation.

According to the residual α gene, either a moderate anemia with splenomegaly (form -α/--) or, in case of type Constant Spring form αnd /--:

-         anemia and jaundice

-         hepatosplenomegaly

-         gallbladder lithiasis

-         risk of thrombotic complications after splenectomy

-         and in the very severe forms,  bone deformities secondary to extramedullary erythropoiesis.

As for the β-thalassemias, treatment is symptomatic, consisting of regular blood transfusions.

4) specific forms of α-thalassemia 

Two syndromes combine an α-thalassemia little symptomatic to a X-linked form of mental retardation 

-         ATR - X acronym for Alpha Thalassemia mental Retardation X- linked syndrome by mutation of the ATRX gene on Xq13.3

-         ATR-16 following a deletion of the telomere 16p with total loss of the locus for α- globin

5) δβ-thalassemias 

Involvement of b and δ chains of the globin due to a more or less extended deletion of both genes.

Clinical picture:

-         heterozygous: asymptomatic with a HbF level of 5-10%

-         homozygous: same clinical picture as Colley disease where there is a high level of HbF with neither HbA nor HbA2

Anesthetic implications:

Minor thalassemias have relatively little specific anesthetic implications: check the level of hemoglobin and platelets count (hypersplenism). 

Severe forms (Cooley disease):

-         risk of difficult intubation if there is hyperplasia of facial bones (rare if the diagnosis and treatment have  been made early)

-         in older children and adolescents: ECG (QT), echocardiography (cardiomyopathy ? pulmonary hypertension ?) and looking for sequelae of hemochromatosis:  hepatic and endocrine functions and cardiac MRI to evaluate the iron overload

-         application of anesthetic precautions recommended for sickle cell disease (see this term).

-         antibiotic prophylaxis

-         thromboprophylaxis especially if the patient is splenectomized, even in case of intermediate form

-         cardiac surgery: increased risk of hemolysis during the cardiopulmonary bypass: priming with blood from the blood bank.

Hemoglobin H is deemed sensitive to oxidants (hemolysis) and hypothermia (precipitation) but adult patients have benefited from a cardiopulmonary bypass with hypothermia without any problem.

References

• Cunningham MJ. 
  Update on thalassemia: clinical care and complications. 
  Pediatr Clin North Am 2008; 55:447-60.
• Rowbottom SJ, Sudhaman DA. 
  Haemoglobin H disease and cardiac surgery. 
  Anaesthesia 1988; 43: 1033-4.
• Massin M, Lê PQ, Damry N. 
  Complications cardiovasculaires des hémoglobinopathies. 
  Percentile 2011 ; 16 : 118-21.
• Staikou C, Stavroulakis E, Karmaniolou I. 
  A narrative review of peri-operative management of patients with thalassaemia. 
  Anaesthesia 2014; 69: 494-510. 
• White K, Blay C, Ataya A, Alnuaimat H, Reddy R.
  A 34-year-old man with bilateral paraspinal masses and shortness of breath.
  Chest 2019: e99-102, doi.org/10.1016/j.chest.2019.05.043

Updated: November 2019