(Sickle cell anemia, sickle cell disease, Hemoglobin S) 

Prevalence: 2-6 % of population in Africa, Asia and around the Mediterranean rim. Chronic hemolytic anemia due to the autosomal dominant transmission of a mutation of the chromosome 11 leading to the synthesis of an abnormal hemoglobin called hemoglobin S (abnormality of globin β: glutamic acid replaced by valine), that precipitates when in its deoxygenated form, leading to sickling of red blood cells and hemolysis (sickle cell crisis).

Heterozygous (AS) patients are said to be carriers of the sickle cell trait: their blood contains 60-65% HbA and 35-40% HbS. The blood of homozygous (SS) patients contains 80-98% HbS and fetal hemoglobin (HbF). 

In the homozygote (SS) form, in situations of hypoxia, HbS polymerizes and precipitates in red blood cells that take an sickle aspect ("sickling"), ending up in hemolysis and formation of thrombosis in small vessels, in particular at the level of the skeleton and viscera, with  very painful downstream infarction (vaso-occlusive crisis). The risk of sickling is very low in the S heterozygotes unless there is association with other hemoglobinopathies: Sβ0 (association with beta-thalassemia with absence of ß globin production) and SC (hemoglobin C that is found in 1-3% of the natives of West Africa), for example. Patients with Sß+ (association with beta-thalassemia where there persists globin ß production ) are less severe because there is sufficient residual production of normal Hb .

Pathophysiology :

Two major mechanisms explain the consequences of the presence of HbS:

-          a "viscosity-vaso-occlusion" phenomena: vaso-occlusive crises following occlusion of microvessels

-          a "hemolysis-dysfunction" phenomena: cerebral thrombosis, glomerulopathy, retinopathy, priapism, pulmonary hypertension, early atherosclerosis: they follow a microvascular damage.

It seems that some children present rather with a vaso-occlusive phenotype (HbSS, HbSβ0 et HbSD) alors ) while others (SS) have a  hemolytic phenotype: they have a higher risk of developing neurological complications and pulmonary hypertension.

Sickling, chronic anemia and hemolysis due to sickle cell disease cause a vascular dysfunction

-         by activating endothelial cells: chronic hypoxemia, endovascular hyperflow linked to anemia, reperfusion with release of free radicals after the occlusive crisis, oxidative stress and chronic inflammation result in intimal hyperplasia (stenosis) and fragmentation of the elastic fibers of the vascular walls (fibrosis)

-         by modifying vasomotricity: the free hemoglobin and arginase-1 produced by hemolysis decrease  the  production of NO

-         causing a hypercoagulability: increase in the activity of factor VIII and von Willebrand antigen, decrease of protein S, increase in platelet adhesion

Clinical signs: 

First signs appear after 6 months of age because HbF prevents the apparition of anemia in newborns and small infants. Symptomatology can be rough, but more often, the children will show signs of chronic hemolytic anemia (palor, jaundice, hepatomegaly, persistent splenomegaly ) especially after the age of 5 years with more or less frequent episodes of acute crises affecting the prognosis.

The possible complications of homozygous sickle cell disease are:

-         sickle-cell crises (vaso-occlusive sickling): painful violent crises secondary to a  intravascular sickling causing tissular infarction; in infants, pain is mostly localized at the extremities ('hands and feet syndrome') 

-         splenic sequestration crises: massive splemegaly and sometimes shock, the most often between 5 months and 2 years of age. 

-         erythroblastopenia crises: often facilitated by bacterial or viral infections (parvovirus B 19 or EBV). 

-         chest pain syndrome : it is a particular complication and one of the most important causes of death in children, particularly in the postoperative period, classically occurring in 15 to 20% of operated children. It is characterized by sudden fever with leukocytosis and severe chest pain.

-         cerebrovascular accidents : peak incidence between 2 and 5 years (the risk is 300 X greater than that of a child not affected by sickle cell disease) which may present as hemiparesis, hemiplegia, aphasia, behavioral disorders, seizures or coma:  11.5% of the sickle cell patients are affected before the age of 18 years. A number of these attacks are however silent and produce a progressive cognitive deterioration. These accidents are mostly ischemic (artery infarction) before the age of 20 years and  hemorrhagic between 20 and 30 years; when the carotid vessels are severely affected, it can evolve to Moya-Moya syndrome (see this term). Measurement of the velocity in cerebral arteries by transcranial Doppler to evaluate the risk of stroke: very low if < 170 cm / sec (= < 1% risk), high if > 200 cm/sec (> 50% of risk within 12 months) and intermediate between these two values. These strokes can be caused by 2 mechanisms: either obstruction of a large or medium size artery (infarction of the downstream territory ) mainly at the cortical level, or ischemia at the junction of two arterial territories ("last meadow"), especially at the level of the white substance. For some unknown reason, the territories that depend on carotid arteries (anterior and middle cerebral arteries) which arethe most affected in case of sickle cell anemia.

-         frequent cholelithiasis 

-         attacks of renal colic in case of papillary necrosis; normal creatinine levels do not rule out the presence of tubular problems (difficulty concentrating urine, K reabsorption)

-         priapism is a classic and severe complication of the disease; it usually occurs between the ages of 5 and 13 years and between 21 and 29 years; it is a low-flow priapism due to obstacles to the venous drainage of the corpora cavernosa.

-         vaso-occlusive crises cause progressive pulmonary fibrosis and vascular occlusions cause ventilatory disorders since adolescence; finally pulmonary arterial hypertension with dysfunction of the RV; this is however rarely symptomatic (9% of severe PAH) but severe cases have a very low life expectancy.

-         dilated cardiomyopathy with congestive heart failure may appear in adolescence due to the combined effects of chronic anemia, circulatory overload, coronary vaso-occlusive crises (but infarctions are rare),  iron overload and of the hemodynamic impact of regional complications (liver, kidney, lung); in the adult, hypertrophic cardiomyopathy and/or high blood pressure have been reported.

Possible treatments:

-        blood transfusions (less than 10 days old collected blood) associated with an oral (deferasirox) or subcutaneous (deferoxoamine) iron chelator; exchange-transfusions with less than 7 days old collected blood.  However, 4 to 11 % of patients suffer a posttransfusion hemolytic reaction after 7 to 10 days: in case of severe form, the red blood cells of both the donor and the recipient are destroyed and this results in a more severe anemia after the transfusion. Those reactions are often misdiagnosed as a drepanocytic crisis because they associate fever, anemia, jaundice, hemoglobinuria and pain. These reactions can be minimized by the administration of corticoids, IV immunoglobulins or prophylactic IV rituximab or eculizimab. The hemolysis could be due to antibibodies that are undetectable before the transfusion (e.g., antibodies directed against rare Rhesus variants, rare in populations from Europa), to accelerated eryptosis of the aged red blood cells of the donor and/or to the presence of cytokines in the recipient’s blood.

-        exsanguinotransfusion with less than 7 days old collected blood

-        cytapheresis for primary or secondary stroke prevention

-        hydroxyurea to reactivate the synthesis of HbF (risk of myelosuppression) and NO production

-        statins for their anti-inflammatory properties at the endothelial level 

-        sildenafil for its vasodilatory effect (NO)

-        thromboprophylaxis

-        bone marrow or stem cell transplantation

Anesthetic implications: 

preoperatively:

-        check hemoglobin level and % HbS:

- if hemoglobin level < 8.5 g/L: transfuse to 10-11 g/L

- if hemoglobin > 8.5 g/L: exchange transfusion to achieve 10-11 g/L (if SS or Sß0) AND HbS < 30 % (if Sß+ or SC)

-        check SpO2  at room air: look for a cardiac cause (pulmonary hypertension ?) if < 94 %

-        recent echocardiography (as early as 5-6 years  of age) to detect a latent PAH: however it is likely that some cases are false positive induced by the increase in  cardiac output due to anemia. Therefore, the tests should best be performed when the hemoglobin level is normal.

-        recent (< 12 months) intracranial Doppler: avoid hyper-hypotension and hyperventilation in case of history of stroke; in case of Moya-moya syndrome: appropriate management (see Moya-moya syndrome)

-        significant risk of obstructive sleep apnea in children under 5-6 years of age (partly related to their ethnic origin)

-        notify the blood bank for blood phenotyping and cross-matching

perioperatively:

-        avoid hypoxemia, acidosis, hypothermia and vascular stasis, maintain normal heart rate

-        peripheral and central venous access can be difficult following repeated transfusions, cytaphereses etc.

-   in case of risk of stroke: avoid low blood pressure, hyperventilation and hypoxia. Cerebral saturation monitoring (NIRS): in SS and Sb0 patients, basal values are lower than in normal or SC or Sb+ patients; moreover, basal values decrease with age and are only partially corrected with blood transfusion.

-        ensure optimal volemia as the renal ability to concentrate urine is reduced: risk of dehydration if oral intakes are insufficient; it could be wise to avoid NaCl 0.9 % as it might favor vasoocclusion.

-        use of a nasopharyngeal tube in case of obstruction of the upper airway

-        antibioprophylaxis because there is an increased risk of infectious complications

-        surgical tourniquet: usefulness to be evaluated on a case-by-case basis; OK if the child has a sufficiently high hemoglobin A level.

-        in case of transfusion: check the level of hemoglobin and bilirubin one week later: delayed transfusion reaction ?

-        thromboprophylaxis

Analgesia: it is advised to avoid corticoids as they seem to increase the risk of a vaso-occlusive crisis (due to the increased leucocytosis). The risk is however decreased after a transfusion.

A retrospective study analyzing the need for analgesics after laparoscopic cholecystectomy in children with sickle cell anemia found that their consumption of morphine by PCA was the double of that of normal children and that their pain scores were higher: this increase in consumption is due in part to chronic pro-inflammatory state caused by sickle cell disease and in part to an increased clearance of morphine in this population.

Transfusion:

as the transfusions are frequent, it is sometimes difficult to find compatible blood. Plan for ABO, Rh and Kell compatibility. In case of previous late hemolytic reaction, it is important to contact the blood bank and an expert in drepanocytosis. In case of acute anemia crisis with fever a few days after a transfusion,  (even with negative cross-matching), the diagnosis of late posttransfusion hemolytic reaction should be raised: do not transfuse without the advice of the hematologist.

In case of cardiac surgery:

• preoperative transfusion  in order to reach a level of HbS less than 30% level
• start your ECC with blood (and remove the patient blood containing HbS)
• if possible, initiate cardioplegia at body temperature
• avoid ECC under hypothermia (maintain body temperature between 32 and 34°C); if hypothermia is essential, ensure that exchange transfusion is complete before getting started

Autologous intraoperative blood recovery favors sickling of the recovered blood and is therefore not recommended.

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Updated: January 2024