A group of inherited hemoglobinopathies that:
- results in a form of Hgb which forms insoluble crystals when in the deoxygenated state
- allows Hgb to polymerize in hypoxic tissues, impairing deformability of the RBC as it passes through microcirculation
Homozygous: nucleic acid substitution on chrom. 11 leads to substitution of val for glu at position 6 of b Hgb chain.
a 2b ), most Hgb is Hgb S = 2a 2b s
follows Mendelian inheritance (off spring of 2 homozygous parents have Ό chance of being normal or disease; and ½ chance of being a homozygous carrier.)
Double heterozygous state: diagnose with electrophoresis
- therefore instead of the 4 normal Hgb chains (Hgb A = 2
- Heterozygous for sickle cell and heterozygous for thalassemia -MCV and MCH are lower than in Homozygous (S-S)
- Heterozygous for sickle cell and heterozygous for Hgb C - tendency to thrombosis and PE, especially in pregnancy
Sickling val allows for a tighter fit between adjacent Hgb molecules than glu, Þ Ý in their natural tendency to polymerize.
ß pO2, Ý pH, and Ý intracellular [Hgb] all of which are sufficient in the kidney, retina and spleen and bone marrow (BM) to regularly promote sickling.
Sickling tendency is ß by presence of non Hgb S therefore sickling tendency in Hgb S homozygous > Hgb S hetero>Hgb S+C
Hemolysis primarily due to reticuloendothelial cell destruction
- Under low pO2 Hgb S forms polymers that form bundles that deform the RBC into elongated sickle shape.
- Sickling is promoted by
Micro-vascular occlusion positive feed back system: polymerization Þ stiff inclusion in RBC membrane Þ impediment of RBC Þ ß pO2 Þ Ý polymerization Þ stasis Þ etc.; can occur acutely or indolently
- spleen is primary site in infancy, undergoes autoinfarction by age 3-4 when phagocytes in BM and liver take over.
Ý risk of sudden death among military recruits
Chronic extravascular hemolytic anemia
Ý Ý retic count
- Confers selective survival advantage to malaria so distribution parallels malarial migration.
- 8% of AA are heterozygous called Sickle Cell trait; while 1:500 are homozygous.
- Mostly asymptomatic
- Occasional hematuria
Microvaso-occlusive complications (infarction) potentially involving all organs of the body
- abnormal RBCs: elongated sickled cells, target cells, oval shaped
- Howell-Jolly bodies (impaired splenic function)
ß pH, dehydration, ß pO2
Infarction: lung, spleen, bone (hips, shoulder, vertebrae, hand foot syndrome), CNS (stroke in 7% of patient)
Lab do not predict who or when this strikes (cells that cause it are not irreversibly sickled)
Treatment: Analgesics (even morphine) and hydration.
Visceral Sequestration Crisis Sickling and pooling of blood within organ Þ exacerbation of anemia
- Types of Crisis:
- Painful V-O crisis: most frequent type; lasting hours, days or weeks; ppt by infection
Aplastic Crisis Due to infection with parvovirus and/or folate deficiency
- Acute chest syndrome: acute and febrile with pulmonary infiltrate on CXR (most common cause of death)
- Treatment: Respiratory support (O2), antibiotics, transfusion therapy.
- Hepatic, girdle and splenic sequestration can require transfusions.
Hemolytic Crisis Ý in rate of hemolysis with ß in Hgb but Ý in retics; usual accompanies a painful crisis
Spleen: spleenomegaly with Howell-Jolly bodies during years 2-3. Afterwards non-palpable due to autoinfarction
- Characterized by a fall in Hgb and retic ct, usually requiring transfusion.
G/U: hypertonic renal medulla Þ Ý sickling Þ (1) impaired concentrating ability and (2) papillary necrosis (leading to hematuria)
- problems with encapsulated bacteria (Pneumococcus, Hemophilus) require prophylactic antibiotic until age 6.
Bones and joints: metacarpal and/ or metatarsal infarction leading to dactylitis causing hand foot syndrome.
- chronic renal failure
- priapism = painful persistent erection
Ý risk of osteomyelitis
Retinopathy over the age of 15-20 years
Skin: Ulcers of the lower leg are common due to vascular stasis and local ischemia
CNS: see Pain crisis: Stroke in children (10% according to syllabus); Intracranial hemorrhage in young adults, spinal cord
Treatment: requires transfusion
- avascular necrosis of the femoral head
Variable, asymptomatic to severe intermitting
- at age 10: 1% today (from 15% 20 years ago)
- at age 20: 10% today (from 50% 20 years ago)
- at age 50: 40% today (from 90% 20 years ago)
Sickle Cell prep: + in S-S or S trait
Prenatal testing is possible
Hgb Electrophoresis is Gold Standard
Ý, Hgb F ß, Hgb S ---
Sicklecell: Hgb A ---, Hgb S Ý
Sickle trait: Hgb A 50%, Hgb S 50%
Prophylactic: avoid precipitating factors: dehydration, anoxia, infection, stasis, cooling of skin
Folic acid (e.g. 5mg/day)
Pneumococcal vaccination and regular oral penicillin to avoid infection.
Crisis: rest, rehydrate, antibiotics in infection, bicarb if acidotic.
Strong analgesics for pain
Blood transfusion on in severe symptomatic anemia, neurological damage, repeated painful or sequestration crisis
Pregnancy and anesthesia: repeated transfusion until Hgb S is less than 30%. Recover to avoid hypoxia and acidosis.
Chelation therapy to avoid iron overloading if repeated transfusion is given
Bone marrow transplant: risks generally outweigh the benefits. Can offer cure to selected patients.
Hydroxyurea Þ Ý Hgb F and ß hemolysis in some patients. Still experimental. Other experimental possibilities include gene therapy (dont hold your breath too long), and drugs targeted at Ý Hgb solubility.