Sickle

Sickle-Cell Anemia

Introduction

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

Symptomatic Variants

Homozygous: nucleic acid substitution on chrom. 11 leads to substitution of val for glu at position 6 of b Hgb chain.

therefore instead of the 4 normal Hgb chains (Hgb A = 2 a 2b ), most Hgb is Hgb S = 2a 2b ^s

follows Mendelian inheritance (off spring of 2 homozygous parents have ¼ chance of being normal or disease; and ½ chance of being a homozygous carrier.)

Double heterozygous state: diagnose with electrophoresis

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

Pathophisiology

Sickling – val allows for a tighter fit between adjacent Hgb molecules than glu, Þ Ý in their natural tendency to polymerize.

Under low pO₂ Hgb S forms polymers that form bundles that deform the RBC into elongated sickle shape.

Sickling is promoted by 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

spleen is primary site in infancy, undergoes autoinfarction by age 3-4 when phagocytes in BM and liver take over.

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

Clinical Aspects

Epidemiology

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

Ý risk of sudden death among military recruits

Chronic extravascular hemolytic anemia

Labs:

Hgb 6-9 g/dl Ý Ý retic count

Peripheral smears:

abnormal RBCs: elongated sickled cells, target cells, oval shaped
Polychromasia
Howell-Jolly bodies (impaired splenic function)

Microvaso-occlusive complications (infarction) potentially involving all organs of the body

Types of Crisis:

Painful V-O crisis: most frequent type; lasting hours, days or weeks; ppt by infection 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

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.

Aplastic Crisis – Due to infection with parvovirus and/or folate deficiency

Characterized by a fall in Hgb and retic ct, usually requiring transfusion.

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

problems with encapsulated bacteria (Pneumococcus, Hemophilus) require prophylactic antibiotic until age 6.

G/U: hypertonic renal medulla Þ Ý sickling Þ (1) impaired concentrating ability and (2) papillary necrosis (leading to hematuria)

chronic renal failure
priapism = painful persistent erection

Bones and joints: metacarpal and/ or metatarsal infarction leading to dactylitis causing hand foot syndrome.

avascular necrosis of the femoral head

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

Disease Course

Variable, asymptomatic to severe intermitting

Mortality:

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)

Diagnosis

Sickle Cell prep: + in S-S or S trait

Prenatal testing is possible

Hgb Electrophoresis is Gold Standard

Normal: Hgb A Ý, Hgb F ß, Hgb S ---

Sicklecell: Hgb A ---, Hgb S Ý

Sickle trait: Hgb A 50%, Hgb S 50%

Treatment

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 (don’t hold your breath too long), and drugs targeted at Ý Hgb solubility.