Sickle cell anaemia: progress in pathogenesis and treatment

Abstract

The phenotypic expression of sickle cell anaemia varies greatly among patients and longitudinally in the same patient. It influences all aspects of the life of affected individuals including social interactions, intimate relationships, family relations, peer interactions, education, employment, spirituality and religiosity. The clinical manifestations of sickle cell anaemia are protean and fall into three major categories: anaemia and its sequelae;pain and related issues; andorgan failure including infection. Recent studies on the pathogenesis of sickle cell anaemia have centred on the sequence of events that occur between polymerisation of deoxy haemoglobin (Hb) S and vaso-occlusion. Cellular dehydration, inflammatory response and reperfusion injury seem to be important pathophysiological mechanisms. Management of sickle cell anaemia continues to be primarily palliative in nature, including supportive, symptomatic and preventative approaches to therapy. Empowerment and education are the major aspects of supportive care. Symptomatic management includes pain management, blood transfusion and treatment of organ failure. Pain managment should follow certain priniciples that include assessment, individualisation of therapy and proper utilisation of opioid and nonopioid analgesics in order to acheive adequate pain relief. Blood selected for transfusion should be leuko-reduced and phenotypically matched for the C, E and Kell antigens. Exchange transfusion is indicated in patients who are transfused chronically in order to prevent or delay the onset of iron-overload. Acute chest syndrome is the most common form of organ failure and its management should be agressive, including adequate ventilation, multiple antibacterials and simple or exchange blood transfusion depending on its severity. Preventitive therapy includes prophylactic penicillin in infants and children, blood transfusion (preferably exchange transfusion) in patients with stroke, and hydroxyurea in patients with frequent acute painful episodes. Bone marrow and cord blood transplantation have been successful modalities of curative therapy in selected children with sickle cell anaemia. Newer approaches to preventative therapy include cellular rehydration with agents that inhibit the Gardos channel or the KCl co-transport channel. Curative gene therapy continues to be investigational at the level of the test tube and transgenic mouse models.

Table I

Beneficial effects of hydroxyurea in patients with sickle cell anaemia

Table II

Factors that contribute to vascular occlusion in patients with sickle cell anaemia

Table III

Unique features of sickle−α-thalassemia (β^s/β^s; -α/-α) compared with sickle cell anaemia without α gene deletion (β^s/β^s; αα/αα)

Table IV

Unique features of pain associated with sickle cell anaemia

Table V

Non-opioid analgesics used in pain management in patients with sickle cell anaemia

Table VI

Non-opioid pharmacological agents commonly used in the management of pain

Table VII

Idiosyncratic (non−prostaglandin-mediated) adverse effects associated with non-steroidal anti-inflammatories

Table VIII

Classification of opioids

Table IX

Adjuvants commonly used in the management of pain in patients with sickle cell anaemia

Table X

Indications for blood transfusion in sickle cell anaemia

Table XI

Desirable features of blood dedicated for transfusion to patients with sickle cell anaemia

Table XII

Complications of sickle cell disease due to therapeutic interventions

Table XIII

Antibacterials commonly used in the treatment of infection in patients with sickle cell anaemia

Fig. 1

Magnetic resonance imaging (MRI) of the brain of a patient with sickle cell anaemia showing an infarct (white area) in the distribution of the middle cerebral artery with gliosis, encephalomalacia and midline shift.

Fig. 2

Magnetic resonance arteriography (MRA) of the brain of the same patient shown in figure 1. It shows multiple microaneurysms (moya moya). The arrows point to two microaneurysms.

Table XIV

Risk factors for acute chest syndrome

Fig. 3

Autopsy specimen of lung from a patient with sickle cell anaemia and fatal acute chest syndrome showing intravascular emboli composed of necrotic bone marrow elements. Hematoxylin & Eosin stain.

Table XV

Renal complications of sickle cell anaemia

Fig. 4

Radiograph of the hip of a patient with sickle cell anaemia showing Ficat Stage III avascular necrosis with extensive subchondral sclerosis and collapse of the femoral head. The arrow shows the site of prior surgical decompression.

Table XVI

Methods of primary molecular and cellular therapy in patients with sickle cell anaemia

Table XVII

Agents that augment fetal haemoglobin production