Sickle Cell Disease, Crises, and Management

HbS is the result of a single base pair change, thymine for adenine at the sixth codon of the beta gene.

This change encodes valine instead of glutamine in the sixth position of the beta globin molecule.

In the study of sickle cell disease, scientists have identified different genetic structures associated with the sickle gene. These structures are recognized by specific patterns of restricted enzyme sites and are known as beta globin haplotypes. Each haplotype is believed to represent independent occurrences of the sickle cell mutation and is named after the places where it was first described.

1. Senegal Haplotype: Found along the Atlantic coast of Africa.
2. Benin Haplotype: Common in Central West Africa, especially in countries like Ghana, Nigeria, and Ivory Coast.
3. Bantu or Central African Republic Haplotype: Prevalent in regions like Cameroon, Zaire, the Central African Republic, Angola, and Kenya.
4. Asian Haplotype: Identified in the Eastern province of Saudi Arabia and Central India.

Sickle cell disease results from the deoxygenation-dependent polymerization of HbS (sickle hemoglobin), leading to the formation of spindle-shaped liquid crystalline bodies called tactoids. These tactoids deform the red blood cells (RBCs) and increase their mechanical fragility, leading to hemolysis, which primarily occurs at extravascular sites.

Key points to understand about the pathogenesis of sickle cell disease:

• The normal diameter of RBCs is approximately 7 microns.
• The diameter of capillaries is about 3 microns.
• Sickling of RBCs occurs at the venous end of capillaries, while unsickling occurs at the arterial end.
• Initially, there are a series of sickle-unsickle cycles.
• Over time, the RBCs can become irreversibly sickled.
• There is an increased adhesiveness of reticulocytes (young RBCs).
• Increased leukocyte (white blood cell) count can lead to thrombotic coagulopathy, contributing to the severity of the disease.

Sickle cell disease is characterized by the abnormal sickling of red blood cells (RBCs) due to the presence of hemoglobin S (HbS). Several factors can enhance the sickling process:

1. Hypoxia: Hypoxia, or low oxygen levels in the blood, is a primary trigger for sickling. When RBCs encounter reduced oxygen, HbS molecules can polymerize, causing RBCs to deform into the characteristic sickle shape.

2. Presence of White Blood Cells (WBC): Elevated white blood cell counts, often seen during infections or inflammatory states, can contribute to sickling. Interactions between WBCs and RBCs may exacerbate the sickling process.

3. Presence of Bacteria: Infections and the presence of bacteria can lead to inflammation and increased sickling. Inflammatory responses further promote the polymerization of HbS, increasing the risk of vaso-occlusive crises.

4. Fever: Elevated body temperature, as seen in fever, can accelerate sickling. Heat exacerbates HbS polymerization, causing RBCs to sickle more readily.

5. Dehydration: Insufficient hydration can lead to a higher concentration of HbS within RBCs, increasing the likelihood of sickling. Proper hydration is essential for minimizing sickling episodes.

6. Metabolic Acidosis: An acidic metabolic environment can promote HbS polymerization and sickling. Conditions leading to metabolic acidosis should be managed carefully in individuals with sickle cell disease.

7. Cold: Cold temperatures can also enhance sickling, particularly through vasoconstriction and reduced oxygen delivery to tissues. Cold exposure may trigger painful episodes in individuals with sickle cell disease.

These factors, individually or in combination, can trigger or exacerbate the sickling of RBCs, leading to vaso-occlusive crises, tissue damage, and other complications associated with sickle cell disease.

Free radicals are molecular or molecular fragments with single unpaired electrons, such as OH and O2-. They are highly reactive and attempt to achieve stability by attracting electrons from other molecules, leading to organ and tissue damage.

Free Radicals in Sickle Cell Disease

The generation of free radicals plays a significant role in tissue damage associated with sickle cell disease (SCD). Here are some key points:

• Free radicals can lead to tissue damage through various mechanisms.
• Lipid peroxidation can alter membrane structure and function, contributing to cell damage.
• Sickled red blood cells (RBCs) often have reduced vitamin E content, making them more susceptible to oxidative stress.
• Spontaneous generation of oxygen radicals occurs in SCD, exacerbating oxidative damage.
• Iron (Fe) can act as a catalyst in the production of the highly destructive OH radical.
• Lipid peroxidation is a common consequence of free radical activity.
• Antioxidants play a crucial role in combating the harmful effects of free radicals by neutralizing them.

Sickle cell disease can lead to various types of crises, each with its own characteristics:

• Vaso-occlusive Crisis: This type of crisis is characterized by the blockage of blood vessels by sickle-shaped red blood cells, leading to pain and tissue damage.
• Haemolytic Crisis: In a haemolytic crisis, there is a sudden accelerated destruction of red blood cells, causing anemia and jaundice.
• Aplastic Crisis: Aplastic crises involve a temporary shut-down of red blood cell production in the bone marrow, leading to severe anemia.
• Acute Sequestration Crisis: This crisis is marked by the rapid pooling of blood in the spleen or liver, which can be life-threatening due to decreased blood volume.
• Megaloblastic Crisis: Megaloblastic crises occur only in individuals with folate deficiency and are characterized by the production of abnormally large and dysfunctional red blood cells.

It's important to note that crises in sickle cell disease are often triggered by infections.

VASO-OCCLUSIVE CRISIS

Vaso-occlusive crisis is a critical aspect of sickle cell disease characterized by:

• Occlusion of blood flow in smaller venules and capillaries due to increased viscosity and sludging caused by sickling of red blood cells.
• Worsening of occlusion due to the increased adhesiveness of sickled reticulocytes.
• Vaso-occlusion serves as the basis for most clinical manifestations of the disease.

Some key features of vaso-occlusive crisis include:

1. The earliest manifestation is dactylitis, resulting from ischemic necrosis of the small bones in the hands and feet.
2. Hand-foot syndrome refers to tender, warm, non-pitting swelling of the dorsa (top surface) of the hands and feet.
3. Recurrent bone pains are the hallmark of vaso-occlusive crisis, with a predilection for affecting long bones. It may also involve the mesenteric vessels.

ACUTE CHEST SYNDROME

Acute chest syndrome is a condition similar to a vaso-occlusive crisis, but it occurs in the lungs due to the occlusion of the microcirculation in the pulmonary bed.

The syndrome is characterized by:

• Progressive respiratory distress and hypoxia
• Chest pain
• Cough
• New infiltrates seen on chest X-ray (CXR)

The etiology of acute chest syndrome is multifactorial and includes:

• Stasis of blood flow
• Hypoventilation
• Fat embolization from bone marrow necrosis
• Micro-thrombi formation in the pulmonary circulation

This condition triggers a massive inflammatory response, capillary leakage may occur, and it can progress to respiratory failure.

The management of acute chest syndrome typically involves:

• Exchange transfusion
• Antibiotics
• Anti-inflammatory therapy
• Respiratory support

HAEMOLYTIC CRISIS

A hemolytic crisis occurs when red blood cells (RBCs) are broken down at a rapid rate, faster than what typically happens during the steady state of the disease.

Key characteristics of a hemolytic crisis include:

• Usually precipitated by infections
• Severe anemia
• Cardiac failure
• Jaundice (yellowing of the skin and eyes)
• Dark-colored urine
• Hepatomegaly (enlarged liver)

In severe cases, a hemolytic crisis can lead to:

• Encephalopathy, which may manifest as seizures
• Altered sensorium (changes in consciousness)

There can be variations of hemolytic crises, including:

• Haemolytic crisis
• Hyperhaemolytic crisis

APLASTIC CRISIS

An aplastic crisis is characterized by a shutdown of the bone marrow, primarily affecting the production of red blood cell precursors.

Key features of an aplastic crisis include:

• Profound anemia due to a marked decrease in red blood cell production
• Possible development of high-output cardiac failure due to severe anemia
• Anemia may recur after blood transfusion until the crisis resolves

Several viruses are associated with causing this syndrome, with Parvovirus B-19 being a notable example. Parvovirus B19 has a specific receptor, the P antigen on erythroid precursors.

Fortunately, in most instances, aplastic crises are self-limiting. However, supportive therapy, including blood transfusions, may be necessary. Steroid treatment can also be beneficial.

ACUTE SEQUESTRATION

Pooling of blood in the spleen is a common occurrence in children with sickle cell anemia, particularly in the first few years of life, resulting in splenic sequestration crisis.

Sequestration crises may also affect the liver.

Sequestration Crisis

The severity of the syndrome associated with sequestration crises can vary widely. It ranges from mild splenomegaly to massive enlargement, circulatory collapse, and, in severe cases, death.

Diagnosing sequestration crises is typically clinical, relying on the observation of spleen enlargement accompanied by a drop in hemoglobin levels of more than 2 g/dl. Imaging studies are rarely required to confirm the diagnosis.

While more common in younger children with HbSS anemia and older children and adolescents with HbSC disease, sequestration crises may occur even in adults.

Children who have experienced one episode of sequestration crisis are at a significantly higher risk of experiencing recurrent events. The morbidity associated with this complication is considerable.

Pathologic changes occur in all organs as a result of the combined effects of chronic hypoxia, recurrent infections, and infarction.

Musculoskeletal System (MSS) Complications

• Osteomyelitis
• Bone infarction/osteonecrosis
• Pathological fractures
• Avascular necrosis
• Chronic leg ulcers
• Digital clubbing

Hepatobiliary Complications

• Hepatomegaly/hepatic necrosis. The latter is due to ischemic damage to the liver.
• Sickle-cell hepatopathy
• Hepatic coma (rare)
• Cirrhosis/haemosiderosis
• Cholelithiasis
• Choledocholithiasis

Genito-Urinary Complications

• Enuresis/polyuria due to hyposthenuria
• Dilute urine that favors bacterial growth
• Pyelonephritis
• Haematuria
• Ischaemic damage to the kidneys
• Progressive azotaemia/renal failure
• Priapism
• Nephrotic syndrome
• Renal medullary carcinoma

Cardiovascular Complications

• Cardiomegaly
• Ischaemic damage to the myocardium
• Congestive cardiac failure
• Cor pulmonale

Respiratory Complications

• Pneumonia
• Pulmonary infarction
• Fat embolism
• Hypoxaemia – due to intrapulmonary R-L shunts, membrane diffusion defects, and a shift of the dissociation curve to the RIGHT
• Restrictive impairment of ventilatory function

Neurologic Complications

• Convulsions…may be due to fever, meningitis, or CVA
• CVA may lead to aphasia, spastic hemiplegia…thrombotic/hemorrhagic
• Incidence of CVA is low in children….0.15% to 1.0%
• Risk factors for infarction….Prior TIA, low steady-state Hb, elevated BP, recent acute chest syndrome

Risk Factors for Intracranial Hemorrhage

• Low steady-state Hb
• High leucocyte count

Ocular Complications

• Dilatation/tortuosity of retinal vessels
• Retinal hemorrhage
• Proliferative retinopathy
• Retinal detachment
• Visual impairment

Endocrinopathies

• Reduced growth hormone from ant. Pituitary
• Reduced cortisol levels
• Pancreatic insufficiency

Management in Steady State

• Record Parameters: Document physical and hematological parameters.
• Avoiding Sickling Factors: Prevent situations or conditions that can trigger sickling of red blood cells.
• Folic Acid Supplementation: Provide folic acid supplements to support red blood cell production.
• Malaria Prophylaxis: Administer preventive measures against malaria, a condition that can exacerbate sickle cell anemia.
• Immunization: Ensure the patient is up-to-date with vaccinations, including pneumococcal, Hib (Haemophilus influenzae type b), and hepatitis B vaccines.
• Antisickling Agents: Medications that help prevent sickling of red blood cells.

Management of Vaso-Occlusive Crisis (VOC)

• Assess Pain: Evaluate the patient's pain using validated pain scales and monitor their reactions during the examination.
• Pain Relief Ladder: Follow the World Health Organization's three-step approach to pain relief based on the reported pain level: mild, moderate, or severe.
  • Step 1: Use non-opioid medications like acetaminophen and NSAIDs.
  • Step 2: Add mild opioids such as codeine.
  • Step 3: Use stronger opioids like morphine for severe pain.

Regular vs. PRN Pain Medication

Administering pain medication regularly on a schedule has been shown to require a lower cumulative dose of analgesia compared to giving medications on an as-needed (PRN) basis. Regular medication helps control pain more effectively because by the time the patient requests medication, a higher dose is often needed to alleviate the pain.

Mild to Moderate Vaso-Occlusive Crisis (VOC)

• Home Care: Bed rest at home.
• Hydration: Encourage liberal oral fluid intake.
• Pain Relief: Administer analgesics, including paracetamol, codeine, and NSAIDs.
• Cause Identification: Identify and treat the underlying cause if known.
• Oxygen: Note that oxygen administration, including hyperbaric oxygen, is generally unhelpful in VOC.

Severe Vaso-Occlusive Crisis (VOC)

• Hospital Admission: Admit the patient to the hospital.
• Pain Management: Administer analgesics based on the severity of pain.
• Intravenous Fluids: Provide intravenous fluids at a rate of 2000-2500ml/m2/24hrs, typically in the form of ½ strength Darrows in 5% dextrose or 4.3% dextrose in 0.18% saline.
• Cause Identification: Identify and treat the underlying cause of the crisis.
• Antimalarials and Antibiotics: Consider administering antimalarial and antibiotic medications until results of appropriate diagnostic tests are available.

Management of VOC - Current Trends

• Patient-Controlled Analgesia (PCA) and Nurse-Controlled Analgesia (NCA): Utilize these techniques for effective pain management.
• Epidural Infusions: Explore the use of epidural infusions for pain relief.
• Psychological Intervention: Consider cognitive and behavioral therapy (CBT) as it can reduce distress associated with pain.
• Cause Identification: Always aim to identify and treat the underlying cause of the crisis.
• Parental Involvement: For younger children, instruct parents on how and when to use pain management pumps. These pumps are typically set to prevent overdose.

MANAGEMENT OF HAEMOLYTIC CRISIS

• Hospital Admission: Admit the patient to the hospital.
• Oxygen Administration: Administer oxygen as needed.
• Transfusion Criteria: Consider blood transfusion in the presence of the following conditions:
  1. Anaemic heart failure.
  2. PCV (Packed Cell Volume) below 15%.
  3. Significant fall in PCV below the steady-state value.
  4. Overwhelming infection.
  5. Use of diuretics.
• Cause Identification: Identify and treat the underlying cause of the haemolytic crisis.

MANAGEMENT OF ACUTE SEQUESTRATION CRISIS

• Treatment of Shock: Elevate the foot of the bed and administer parenteral steroids (methylprednisolone or hydrocortisone).
• Blood Transfusion: Consider packed cell transfusion at a rate of 5-10 ml/kg.
• Important Note: Some sequestered cells may return to the circulation.
• Partial Exchange Blood Transfusion (E.B.T.): This may be required in some cases.
• Splenectomy: Splenectomy (surgical removal of the spleen) may be considered in the following indications:
  1. Recurrent acute splenic sequestration crisis.
  2. Hypersplenism.
  3. Splenic abscess.
  4. Massive splenic infarction.

MANAGEMENT OF APLASTIC CRISIS

• Intermittent Oxygen: Provide intermittent oxygen as needed.
• Whole Blood Transfusions: Consider whole blood transfusions.
• Steroid Therapy: Steroid therapy may be beneficial.
• Bone Marrow Transplantation: In severe cases, bone marrow transplantation may be considered.

MANAGEMENT OF INFECTIONS

• Common Organisms: Common organisms involved include H. influenzae, pneumococcus, salmonella spp., and S. aureus.
• Choice of Antibiotics: Antibiotic choices may include:
  • Chloramphenicol + Erythromycin
  • Xtalline penicillin + Chloramphenicol
  • Chloramphenicol + Cloxacillin
  • Cephalosporins
  • Macrolides
• Penicillin Prophylaxis/Pneumococcal Vaccine: Routine penicillin prophylaxis and pneumococcal vaccines are not recommended because splenic function is preserved in African patients with SCA due to continuous stimulation by malaria.

Management of Leg Ulcers

• Bed Rest: Recommend bed rest.
• Elevation of Affected Limb: Elevate the affected limb.
• Daily Eusol / Zinc Sulphate Dressings: Apply daily Eusol or zinc sulfate dressings.
• Maintenance Transfusion: Consider maintenance transfusion as part of management.
• Oral Zinc Sulphate: Administer oral zinc sulfate.
• Epanutin: Epanutin may be prescribed.
• Skin Grafting: Skin grafting may be necessary in some cases.

Management of Priapism

• Sedatives/Anxiolytics: Administer sedatives or anxiolytics.
• Analgesics: Provide analgesics for pain relief.
• Intracavernous Injection of Adrenergic Agonists: Consider intracavernous injection of adrenergic agonists, e.g., Etilefrine.
• Phosphodiesterase Type 5 Inhibitors: Phosphodiesterase type 5 inhibitors such as sildenafil, given orally, can help prevent recurrence.
• Exchange Blood Transfusion (E.B.T): E.B.T may be necessary.
• Surgery: Caverno-spongiosum anastomosis may be performed as a surgical option.

Management of Haematuria

• Spontaneous Resolution: Haematuria usually stops spontaneously.
• Conservative Treatment: Conservative treatment may include:
  • Liberal fluids to reduce clot formation.
  • Correction of anaemia.
  • Epsilon Amino Caproic Acid:

Management of Ocular Complications

• Laser Photocoagulation: Consider laser photocoagulation for proliferative retinopathy.

CNS Infarction

• Long-term Programme of Partial EBT or Hypertransfusion: Initiated, especially if there is evidence of permanent endothelial damage on angiography or CT/MRI scan.
• Aim: To permanently reduce sludging by decreasing viscosity.
• Transcranial Doppler (TCD): Can be used to monitor cerebral blood flow and predict those who are liable to stroke.
• Increased Blood Flow Velocity in Cerebral Arteries: Greater than 200cm/sec diagnosed by TCD is an indication for initiation of transfusions to maintain HbS below 30%.

Indications for Chronic Transfusion Therapy

1. CVA
2. Children with Abnormal TCDs
3. Recurrent Acute Chest Syndrome
4. Severe Debilitating Pain
5. Chronic Organ Failure

Avascular Necrosis

• Total Hip Replacement with Prostheses.

Antisickling Agents

• Induction of HbF Synthesis:
• Hydroxyurea: 15mg/kg/24 hrs. Gradually increase to max of 30mg/kg/24hrs. Monitor FBC, LFT, and HbF. Increase in HbF is usually 10-15%
• Recombinant Human Erythropoietin (rhEPO)
• Resveratrol: A natural dietary polyphenol.
• Butyric Acid
• Fagara Zanthoxyloides (Zanthoxylum Zanthoxyloides) – 2-Hydroxymethyl Benzoic Acid
• Ceteidil
• Ciklavit

1. Genetic:
   • Persistent increase in HbF (Fetal Hemoglobin) - This is a positive genetic factor that indicates a better prognosis. Higher levels of HbF can mitigate the effects of sickle cell anemia.
   • Presence of HbC/B-thal - The presence of certain hemoglobin variants like HbC or B-thalassemia can influence the course of the disease.
   • ?haplotype - Genetic haplotypes can also play a role in disease severity, but this aspect may not be fully understood.
2. Environmental:
   • Social class - The socioeconomic status of individuals can impact access to healthcare and overall health outcomes.
   • Early diagnosis - Identifying sickle cell anemia at an early stage through newborn screening or other means allows for timely interventions.
   • Good nutrition, availability of health facilities, equable climate, protection from malaria - These environmental factors can influence the well-being of individuals with sickle cell anemia.
3. Unknown: It's important to note that despite genetic and environmental factors, there can be variations in disease severity among siblings or individuals living in similar environments. Some aspects of these differences remain unknown.

Sickle Cell Disease (SCD) is a hereditary condition, and preventive measures are essential for at-risk individuals. Genetic counseling plays a pivotal role in managing SCD risk and making informed decisions. The counseling process involves:

Genetic counseling is a process that involves educating individuals, couples, and families about the genetic aspects of Sickle Cell Disease and its transmission. Here's an outline of how genetic counseling is typically conducted:

1. Evaluation: The genetic counselor assesses the individual's or couple's medical history, family history, and ethnicity to determine their risk of carrying the SCD gene.
2. Educational Session: The counselor provides information about SCD, its inheritance pattern, and the likelihood of passing the SCD gene to offspring. This session helps individuals understand the genetic basis of the disease.
3. Carrier Testing: Genetic testing may be recommended to determine if an individual or couple carries the SCD gene. This test can help identify carriers of the gene, known as carriers or trait carriers, who do not have the disease but can pass it on to their children.
4. Risk Assessment: Based on the test results and family history, the counselor assesses the risk of having a child with SCD if both partners are carriers.
5. Family Planning: The counselor discusses family planning options, including the likelihood of having an affected child, the available prenatal testing options, and reproductive choices.

Prenatal Diagnosis: For couples identified as carriers or at risk of having a child with sickle cell disease, prenatal diagnosis is an option. This involves medical tests during pregnancy to determine whether the fetus has the disease. If the diagnosis confirms the presence of sickle cell disease and the parents choose to do so, selective abortion may be considered. This decision is deeply personal and should be made in consultation with healthcare professionals.

Neonatal Screening: Routine neonatal screening is a critical part of sickle cell disease prevention. This screening typically occurs shortly after birth and involves a blood test to check for the presence of abnormal hemoglobin. Modern techniques, such as High-Performance Liquid Chromatography (HPLC) and Isoelectric Focusing (IEF), have greatly improved the accuracy and efficiency of neonatal screening. When family studies indicate that both parents are carriers, neonatal screening can provide an early diagnosis, enabling prompt medical intervention and management.