Sickle cell disease

Created 19/12/2021, last revision 17/01/2023

Pathophysiology

sickle cell disease (SCD) is an autosomal recessive (AR) inherited disorder of the group of hemoglobinopathies, which is manifested by a change in the shape of erythrocytes into elongated sickles
- HbS is caused by the substitution of glutamic acid for valine at the 6th amino acid of the β-globin chain (β6 Glu→Val), caused by a point mutation in the β-globin gene
- if a person carries one healthy gene and one HbS gene (heterozygote), he is a carrier who usually has no health issues
  - HbS makes up < 50% of the erythrocyte´s hemoglobin (most commonly 40%). The rest is normal hemoglobin (mainly HbA) which protects the individual against sickle cell disease
- a person with two HbS genes (HbSS) is called a homozygote, cannot produce normal hemoglobin, and develops clinical manifestations of sickle cell anemia
  - SCD can also occur in people who have one sickle cell gene and one of the other hemoglobinopathies
the homozygote´s hemoglobin has different properties ⇒ unoxygenated hemoglobin aggregates, which leads to erythrocytes deformation
the disease manifestations usually start in childhood (from about one year of age), especially in people from tropical and subtropical areas where malaria is also common

blood stagnation ⇒ hypoxia

aggregation of blood cells in blood vessels ⇒ ischemia and infarcts

increased destruction of blood cells in the spleen ⇒ anemia

human hemoglobin is a tetramer consisting from 2 pairs of polypeptide (globin) chains ⇒ 2 dimers
the dimers are formed in definitive erythropoiesis by the combination of one α and one non-α chain (β, γ, or δ)
each chain surrounds a heme, which is located in a heme pocket
the heme is a protoporphyrin formed by four pyrrole nuclei – tetrapyrrole. In the center of the tetrapyrrole nucleus is a hexavalent and divalent iron ion, which can reversibly bind an oxygen molecule. This allows hemoglobin to perform its primary function – transfer of oxygen from lungs to tissues

hemoglobinopathies are inherited diseases caused by a defect in the formation of one or more globin chains
caused by mutations or deletions in the genes encoding the globin chains

diseases with a defect in the structure of the globin chain
- sickle cell disease (SCD)
- methemoglobinemia
diseases with defects in globin chain synthesis
- thalassemia

large-artery vasculopathy affecting the intracranial segments of the internal carotid arteries (ICA) and proximal middle cerebral arteries (MCA) due to intimal hyperplasia caused by repeated traumatic injury, inflammation, and a hypercoagulable state
progressive involvement of the arteries of the Circle of Willis leads to Moyamoya syndrome, which predisposes to both ischemic stroke and hemorrhage
silent strokes typically occur in the territory of the penetrating arteries

babies usually have no particular symptoms after birth
the first symptoms rarely appear until around the first year of life, when hemoglobin S forms in their bodies
early symptoms include pain and swelling in the arms and legs

manifestations of sickle cell disease are variable
- from mild discomfort to severe complications
- homozygotes tend to have worse symptoms, while heterozygotes are perfectly fine until their oxygen levels drop, which can be caused, for example, by dehydration, intense physical exertion, or staying at high altitudes
symptoms (both acute and chronic) resulting from ischemia – sickle-shaped erythrocytes block the arterioles
- ischemic stroke (typically in children, the radiologic appearance of moyamoya syndrome with possible secondary hemorrhages)
- pulmonary microinfarcts
- muscle pain
- bone necrosis
- papillary renal necrosis with hematuria, microalbuminuria, and proteinuria worsening with age and often ending in uremia
- skin ulceration, etc.
hemolytic anemia with increased reticulocyte count
vaso-occlusive sickle cell crises
- sudden attacks of severe, prolonged bone and muscle pain provoked by, e.g., exposure to high altitude, impaired lung function, increased metabolic activity, and dehydration
- individual crises usually resolve within a few days or even weeks; frequency varies (once a year to daily)
dysfunctional spleen (autosplenectomy) – consequence of infarcts and infections → more here

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no data from randomized trials on antithrombotic therapy in secondary prevention
- caution is advised because of the increased risk of bleeding
antithrombotic drugs are recommended in the presence of comorbidities (e.g., atherosclerosis, dissection, etc.)