Sickle Cell Disease

A genetic condition that results in sickle, or crescent, shaped red blood cells

Pathophysiology

1. Haemoglobin is responsible for binding oxygen in red blood cells, and therefore carrying oxygen around the body.
    
2. Haemoglobin is made of:
   1. Haem: The iron part of haemoglobin
   2. Globin: 4 polypeptides (chains of amino acids), each one being complexed with a haem group
       
3. There are different types of globin chains, and depending on the combination of them, it influences the type of ‘overall’ haemoglobin you get.
   1. HbA: The most common type of haemoglobin form is made of 2 alpha chains and 2 beta chains.
   2. HbA2: 2 alpha chains, 2 delta chains
   3. HbF: Foetal haemoglobin is made of 2 alpha chains and 2 gamma chains
       
4. In sickle cell disease, you get a mutation in the gene encoding the beta-globin chains on chromosome 11, resulting in HbS formation – as a consequence, you get no HbA formation, and HbS replaces HbA.
    
5. Sickle cell disease is inherited in an autosomal recessive pattern. If you have both copies, you have sickle cell disease. If you only have one, you have sickle cell trait.
    
6. Interestingly, sickle cell trait confers a degree of protection against severe malaria. It’s therefore quite common in areas where malaria is usually endemic e.g. Africa and parts of the Middle East.
    
7. People with sickle cell disease have sickle (crescent) shaped red blood cells which cause problems because they cause the following:
   1. Vaso-Occlusion: The cells can clump together easily which occludes blood vessels and can cause hypoxia wherever they’re blocking vessels
   2. Sterile Inflammation: This basically refers to a non-infective inflammatory process. It’s thought to happen due to reperfursion injuries that occur with vaso-occlusion as well as the release of local inflammatory factors from vaso-occlusion.
   3. Endothelial Dysfunction: These sickle shaped RBCs are quite fragile so they lyse easily, resulting in a chronic haemolytic anaemia

The National Heart, Lung, and Blood Institute (NHLBI), Public domain, via Wikimedia Commons

Sickle Cell Disease Pathophysiology

Clinical Features

In the UK, the national screening programme includes screens for sickle cell anaemia. However, if it is not diagnosed post-natally, the condition may manifest as a progressive anaemia once foetal haemoglobin starts being replaced by HbS.

The clinical features of sickle cell disease are described with the term sickle cell crisis. They refer to the various conditions that arise secondary to vaso-occlusion, sterile inflammation, and endothelial dysfunction.

• Vaso-Occlusive Crisis: Pain arising from ischaemia and hypoxia due to clumped sickle cells obstructing blood vessels. Triggers include cold, physical exertion, and dehydration. This can happen anywhere, and this can result in:
  • Long bone pain: From microvascular occlusion in the bone marrow
  • Abdominal pain: From mesenteric ischaemia
  • Pelvic Pain
  • Dactylitis: Hands and feet becoming affected
  • Priapism: Persistent and painful erection due to accumulation of blood in the penis – this requires emergency aspiration of blood to treat

• Acute Chest Syndrome: A group of signs and symptoms that are thought to occur from a specific trigger e.g. infection, pulmonary infarction, or fat emboli causing sickled blood cells to adhere to pulmonary microvasculature which kind of results in vaso-occlusive crisis in the lungs. This is a severe complication of sickle cell disease and can result in death.
  • Cough
  • Chest Pain
  • Fever
  • Dyspnoea
  • Desaturation
  • Oxygen requirement
  • Wheeze/crackles on auscultation
  • Pulmonary infilitrate on chest x-ray
  • Respiratory failure if not treated
     
• Cerebrovascular Accident: Patients with sickle cell disease have an increased risk of developing stroke. 
   
• Functional Asplenia: The spleen usually infarcts early in life (<2 years of age), resulting in a functional asplenia which confers an increased risk of developing infections.
   
• Avascular Necrosis: Occurs commonly in the femoral/humeral head but can occur anywhere. Occurs due to loss of blood supply.
   
• Osteomyelitis: Due to the functional asplenia (and thus immunocompromise), and presence of potentially infarcted bone from avascular necrosis, there is a risk of osteomyelitis as well.
   
• Splenic Sequestration: Thought to occur from sickled cells obstructing a larger draining vein of the spleen, resulting in obstruction of outflow from the spleen. This eventually results in accumulation of blood in the spleen.
  • Painful and enlarged spleen
  • Anaemia due to blood accumulating in the spleen (this can be acute and very dangerous)
  • Shock, again because blood starts to accumulate in the spleen
     
• Aplastic Crisis: This happens when there’s an infection with B19 parvovirus. It causes a sudden reduction in bone marrow function, so you get reduced red blood cell production – patients might need blood transfusions in these instances.
   
• Anaemia: Fatigue, pallor, breathlessness, lightheadedness
   
• Fat Embolism: This can occur from necrosis of the bone marrow – this can result in pulmonary embolism/stroke

Chronic Problems

• Eye disease: Due to chronic occlusion of the retinal vasculature, you can get a proliferative retinopathy resulting in blurred vision, floaters, and potentially sudden vision loss.
• Chronic kidney disease: Impaired blood flow to the kidney
• Pulmonary Hypertension: From in situ thrombosis that develops, increasing pulmonary vascular resistance
• Gallstones: From excess bilirubin secondary to haemolysis

Investigations

Bedside

• ECG: To rule out cardiac causes of presentation

Bloods

• FBC: Anaemia. May also show raised white cell count if there’s an infection
• U&Es: For renal function for chronic kidney disease
• LFTs: Since you get a haemolytic anaemia, you may see raised levels of bilirubin. Chronic blood transfusions can also cause deranged LFTs
• G&S and Cross Match: In case someone requires transfusion
• Cultures: Blood/urine/sputum to rule out infection
   

Prof. Osaro Erhabor, CC0, via Wikimedia Commons

Sickle Cell Disease Blood Film

Imaging

• CXR: For lung infiltrates in acute chest syndrome
• Joint XR: To rule out avascular necrosis
• CT Scan: Particularly if concerned about the acute surgical abdomen as a differential for presentation
• Transcranial Doppler Studies: To assess stroke risk in children

Management

Conservative

• Supportive: A lot of managing sickle cell crisis in supportive management with fluids, oxygen, warm environment etc

Medical

• Analgesia:
  • Sickle cell crisis can be exceptionally painful – NICE guidelines recommend offering patients opiate alongside regular paracetamol and NSAIDs
  • Patient controlled analgesia (PCA) may also be a suitable idea
• Blood Transfusions: May be required in people with severe anaemia or in certain crises e.g. splenic sequestration crisis
• Hydroxycarbamide: This is used when people have frequent sickle cell crises. It works by increasing production of HbF
• Crizanlizumab: Works by inhibiting interactions between various cells to prevent cells from obstructing
• Prophylactic Vaccination: Due to hyposplenism

Surgical/Other

• Splenectomy: For recurrent splenic sequestration
• Bone marrow or stem cell transplants
• Genetic Testing: Can be offered alongside genetic counselling to assess the likelihood of offspring having sickle cell disease/trait

National Heart Lung and Blood Insitute (NIH), Public domain, via Wikimedia Commons

Inheritance Pattern of Sickle Cell Disease

Prophylactic

• Long-term antibiotics: Usually penicillin prophylaxis with phenoxymethylpenicillin or erythromycin in penicillin allergic people
• Vaccinations: Childhood vaccines (meningitis, pneumococcal etc), annual influenza vaccine, hepatitis B vaccines

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053558/

https://www.nice.org.uk/guidance/cg143/chapter/Recommendations#possible-acute-complications

https://www.ncbi.nlm.nih.gov/books/NBK482384/

https://www.nhs.uk/conditions/sickle-cell-disease/symptoms/

https://www.ncbi.nlm.nih.gov/books/NBK553164/

https://cks.nice.org.uk/topics/sickle-cell-disease/management/prevention-of-complications/