Analysis of Sickle Cell Disease

SICKLE CELL DISEASE

Sickle-cell disease (SCD), also known as sickle-cell anemia (SCA), is a hereditary blood disorder, caused by an abnormality in the oxygen-carrying protein hemoglobin found in red blood cells. This leads to a propensity for the cells to assume an abnormal, rigid, sickle-like shape under certain circumstances.

Sickle-cell disease occurs when a person inherits two abnormal copies of the hemoglobin gene, one from each parent. Several subtypes exist, depending on the exact mutation in each hemoglobin gene. A person with a single abnormal copy does not experience symptoms and is said to have sickle-cell trait. Such people are also referred to as carriers.

Hemoglobin S (Hb S) is the result of a single base-pair change, thymine for adenine, at the sixth codon of the β globin gene. This change encodes valine instead of glutamine in the sixth position in the β globin molecule. Sickle cell anemia, homozygous Hb S, occurs when both β globin genes have the sickle cell mutation.

HbS (226 GluVa1) polymerizes reversibly when deoxygenated to form a gelatinous network of fibrous polymers that stiffen the RBC membrane, increase viscosity, and cause dehydration due to potassium leakage and calcium influx producing sickle-shaped RBCs. The following are the resulting problems:

These changes also produce the sickle shape.

1. Less the pliability needed to traverse small capillaries leading to altered "sticky" membranes that are abnormally adherent to the endothelium of small venules (This venoocclusive component usually dominates the clinical course)
2. Episodes of microvascular vasoocclusion
3. Premature RBC destruction (hemolytic anemia) because the spleen destroys the abnormal RBC.
4. The rigid adherent cells clog small capillaries and venules, causing;
5. Tissue ischemia,
6. Acute pain, and

• Gradual end-organ damage.

1. Prominent manifestations include

• Episodes of ischemic pain (i.e., painful crises)
• Ischemic malfunction or frank infarction in the

1. Spleen,
2. Central nervous system,

• Bones,

1. Liver,
2. Kidneys, and
3. Lungs

Sickle cell disease refers to not only patients with sickle cell anemia but also to compound heterozygotes where one β globin gene mutation includes the sickle cell mutation and the second β globin allele includes a gene mutation other than the sickle cell mutation, such as;

• Mutations associated with Hb C,
• Hb S β-thalassemia,
• Hb D, and
• Hb O Arab

Table 104-2 Clinical Features of Sickle Hemoglobinopathies

Condition Clinical Abnormalities Hemoglobin Level g/L (g/dL) MCV, Fl Hemoglobin Electrophoresis Sickle cell trait None; rare painless hematuria Normal Normal Hb S/A:40/60 Sickle cell anemia Vaso occlusive crises with infarction of spleen, brain, marrow, kidney, lung; aseptic necrosis of bone; gallstones; priapism; ankle ulcers 70–100 (7–10) 80–100 Hb S/A:100/0   Hb F:2–25% S/° thalassemia Vaso occlusive crises; aseptic necrosis of bone 70–100 (7–10) 60–80 Hb S/A:100/0   Hb F:1–10% S/+ thalassemia   Hemoglobin SC Rare crises and aseptic necrosis   Rare crises and aseptic necrosis; painless hematuria 100–140 (10–14)   100–140 (10–14) 70–80   80–100 Hb S/A:60/40   Hb S/A:50/0 Hb C:50%

In sickle cell anemia, Hb S is commonly as high as 90% of the total hemoglobin.

In sickle cell disease, Hb S is >50% of all hemoglobin.

Clinical Manifestations and Treatment of Sickle Cell Anemia/Crises

• Abnormal immune function

As early as 6 months of age, they may have functional asplenia predisposing them to Bacterial sepsis. This is one of the greatest causes for morbidity and mortality in this patient population. Bactria are;

1. Streptococcus pneumoniae and
2. Haemophiles influenzae type B.

Children with sickle cell anemia should receive prophylactic oral penicillin V until at least 5 yr. of age (125 mg twice a day up to age 3 yr., and then 250 mg twice a day).

1. Human parvovirus B19 poses a unique threat for patients with sickle cell anemia because such infections limit the production of reticulocytes. Any child with reticulocytopenia should be considered to have parvovirus B19 until proved otherwise. Acute infection with parvovirus B19 is associated with red cell aplasia (aplastic crisis), fever, pain, splenic sequestration, acute chest syndrome (ACS), glomerulonephritis, and strokes.

• Fever and Bacteremia

Fever in a child with sickle cell anemia is a medical emergency, requiring prompt medical evaluation and delivery of antibiotics due to the increased risk of bacterial infection and concomitant high fatality rate with infection. Several clinical management strategies have been developed for children with fever, ranging from admitting all patients with a fever for IV antimicrobial therapy to administering a 3rd-generation cephalosporin in an outpatient setting to patients without any of the previously established risk factors for occult bacteremia.

• Dactylitis

Dactylitis, often referred to as hand-foot syndrome, is often the first manifestation of pain in children with sickle cell anemia.

Occurring in 50% of children by their 2nd year.

Dactylitis often manifests with symmetric or unilateral swelling of the hands and/or feet. Unilateral dactylitis can be confused with osteomyelitis, and careful evaluation to distinguish between the two is important, because treatment differs significantly.

Dactylitis requires palliation with pain medications, such as acetaminophen with codeine, whereas osteomyelitis requires at least 4-6 wk. of IV antibiotics.

• Splenic Sequestration

Acute splenic sequestration is a life-threatening complication occurring primarily in infants and can occur as early as 5 wk. of age. Approximately 30% of children with sickle cell anemia have a severe splenic sequestration episode, and a significant percentage of these episodes are fatal.

The etiology of splenic sequestration is unknown.

Clinically, splenic sequestration is associated with;

1. Engorgement of the spleen,
2. Subsequent increase in spleen size,
3. Evidence of hypovolemia, and
4. Decline in hemoglobin of ≥2 g/dl from the patient's baseline hemoglobin; reticulocytotic and a decrease in the platelet count may be present.
5. May have upper respiratory tract infections, bacteremia, or viral infection.

Treatment of splenic sequestration

Early intervention and maintenance of hemodynamic stability using isotonic fluid or blood transfusions. If blood is required, typically 5 mL/kg of packed red blood cells (RBCs) is given. Repeated episodes of splenic sequestration are common, occurring in ~50% of patients. Most recurrent episodes develop within 6 mo. of the previous episode. Prophylactic splenectomy performed after an acute episode has resolved is the only effective strategy for preventing future life-threatening episodes. Although blood transfusion therapy has been used to prevent subsequent episodes, evidence strongly suggests this strategy does not reduce the risk of recurrent splenic sequestration when compared to no transfusion therapy.

• Pain

The cardinal clinical feature of sickle cell anemia is pain.

The pain is characterized as unremitting discomfort that can occur in any part of the body but most often occurs in the;

1. Chest,
2. Abdomen, or
3.  

The exact etiology of pain is unknown, but the pathogenesis is initiated when blood flow is disrupted in the microvasculature by sickle cells, resulting in tissue ischemia.

Precipitating causes of painful episodes can include;

1. Physical stress,
2. Infection,
3. Dehydration,
4. Hypoxia,
5. Local or systemic acidosis,
6. Exposure to cold, and
7. Swimming for prolonged periods.

Successful treatment of painful episodes

• Counseling the parents
• Specific therapy for pain varies greatly but generally includes the use of acetaminophen or a nonsteroidal agent early in the course of pain, followed by escalation to acetaminophen with codeine or a short- or long-acting oral opioid.
• IV morphine or derivatives of morphine.
• Hydroxyurea, a myelosuppressive agent, is the only effective drug proved to reduce the frequency of painful episodes.
• Priapism

Priapism is defined as an involuntary penile erection lasting for longer than 30 minutes and is a common problem in sickle cell anemia. The persistence of a painful erection beyond several hr. suggests priapism. On examination;

• The penis is erect.
• The ventral portion and the glans of the penis are typically not involved, and their involvement necessitates urologic consultation based on the poor prognosis for spontaneous resolution.

Priapism occurs in 2 patterns;

1. Stuttering; self-limiting, intermittent bouts of priapism with several episodes over a defined period
2. Refractory; as prolonged priapism beyond several hours with both types occurring in patients from early childhood to adulthood.

The optimal treatment for priapism is unknown, but treatment strategies can be divided into acute treatment and preventive therapy.

1. For acute treatment,
   1. Supported therapy, such as sitz bath or pain medication, is commonly employed.
   2. Priapism lasting >4 hr. should be treated by aspiration of blood from the corpora cavernosa followed by irrigation with dilute epinephrine to produce immediate and sustained detumescence.

• Urology consultation is required to initiate this procedure, with appropriate input from a hematologist.

1. Either simple blood transfusion therapy or exchange transfusion has been proposed for the acute treatment of priapism. However, evidence suggests that exchange transfusion therapy is not effective in enhancing detumescence.

1. For the prevention of recurrent priapism,
   1. Hydroxyurea appears to have promise; the use of etilefrine, a sympathomimetic amine with both α1 and β1 adrenergic effects, appears safe and promising in the secondary prevention of priapism. The long-term effects of recurrent or prolonged priapism episodes in prepubertal children are not known. In adults, infertility and impotence are potential consequences.

• Neurologic Complications

Overt and silent strokes in approximately 11% and 20% of children with sickle cell anemia respectively before their 18th birthday. An overt stroke is defined as a focal neurologic deficit lasting >24 hr.

However, this definition is outdated because many patients with sickle cell anemia will be treated with blood therapy that can hasten their recovery to baseline. A more functional definition is the presence of a focal neurologic deficit that lasts for >24 hr. and/or increased signal intensity with a T2-weighted MRI of the brain indicating a cerebral infarct, corresponding to the focal neurologic deficit. The definition of silent cerebral infarct is the absence of a focal neurologic deficit lasting >24 hr. in the presence of a lesion on T2-weighted MRI indicating a cerebral infarct. Evidence of a stroke can be found as early as 1 yr. of age. Other neurologic complications include headaches that may or may not be related to sickle cell anemia, seizures, cerebral venous thrombosis, and reversible posterior leukoencephalopathy syndrome (RPLS). Children with other types of sickle cell disease such as Hb SC or Hb Sβ-thalassemia plus might have overt or silent cerebral infarcts as well.

Clinical Manifestations of Sickle Cell Anemia (Harrison and Wikipedia)

1. Vaso-occlusive crisis

Caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in;

1. Ischemia
2. Pain
3. Necrosis
4. Often organ damage

Painful crises are treated with:

1. Hydration,
2. Analgesics, and pain management requires opioid administration at regular intervals until the crisis has settled or NSAIDs (such as diclofenac or naproxen) if not very severe.
3. Blood transfusion
4. Splenic sequestration crisis
5. Acute chest syndrome

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms:

1. Chest pain,
2. Fever,
3. Pulmonary infiltrate or
4. Focal abnormality,
5. Respiratory symptoms, or
6. Hypoxemia.

It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with Vaso-occlusive crises then they develop ACS. Nevertheless, about 80% of patients have Vaso-occlusive crises during ACS.

4. Aplastic crisis

Is acute worsening of the patient's baseline anemia, producing

1. Pale appearance, 
2. fast heart rate, and

• Fatigue.

This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. 

Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in hemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.

5. Hemolytic crisis

Hemolytic crises are acute accelerated drops in hemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency. Management is supportive, sometimes with blood transfusions.

Management of SCD (Wikipedia)

1. Folic acid and penicillin

These patients take a 1 mg dose of folic acid daily for life.

From birth to five years of age, they also have to take penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses.

2. Malaria chemoprophylaxis

The protective effect of sickle-cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. It has therefore been recommended that people with sickle-cell disease living in malarial countries should receive anti-malarial chemoprophylaxis for life.

3. Vaso-occlusive crisis

Pain management requires opioid administration at regular intervals until the crisis has settled.

For milder crises, a subgroup of patients manages on NSAIDs (such as diclofenac or naproxen).

4. Acute chest crisis
5. Fluids
6. Antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),

• Oxygen supplementation for hypoxia, and

1. Close observation.
2. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated.
3. The patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission
4. Hydroxyurea

Shown to:

1. Decrease the number and severity of attacks
2. Increase survival time

This is achieved, in part, by reactivating fetal hemoglobin production in place of the hemoglobin S that causes sickle-cell anemia.

Long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.

6. Transfusion therapy

Decreases the number of red blood cells (RBC) that can sickle by adding normal red blood cells reducing the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal increased cerebral blood flow velocities.

7. Bone marrow transplants

Bone marrow transplants have proven effective in children. Bone marrow transplants are the only known cure for SCD. However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a twin family member (syngeneic) or close relative (allogeneic) would donate the bone marrow necessary for transplantation.

Complications

1. Increased risk of severe bacterial infections
2. Stroke,
3. Silent stroke 
4. Cholelithiasis (gallstones) and cholecystitis may result from excessive bilirubin production and precipitation due to prolonged hemolysis.
5. Avascular necrosis (aseptic bone necrosis) of the hip and other major joints
6. Decreased immune reactions due to hypersplenism (malfunctioning of the spleen)^[45]
7. Priapism and infarction of the penis^[46]
8. Osteomyelitis (bacterial bone infection), the most common cause of osteomyelitis in SCD is Salmonella 
9. Opioid tolerance
10. Acute papillary necrosis in the kidneys
11. Leg ulcers
12. In eyes,
    1. Background retinopathy,
    2. Proliferative retinopathy,
    3. Vitreous hemorrhages, and
    4. Retinal detachments can result in blindness.
13. During pregnancy, 
    1. Intrauterine growth retardation,
    2. Spontaneous abortion, and 
    3. pre-eclampsia
14. Chronic pain: Even in the absence of acute Vaso-occlusive pain, many patients have unreported chronic pain.
15. Pulmonary hypertension (increased pressure on the pulmonary artery) can lead to strain on the right ventricle and a risk of heart failure;
16. Chronic kidney failure due to sickle-cell nephropathy manifests itself with

Prognosis

About 90% of patients survive to age 20, and close to 50% survive beyond the fifth decade. In 2001, according to one study performed in Jamaica, the estimated mean survival for sickle-cell patients was 53 years old for men and 58 years old for women with homozygous SCD.