blood and immune - ciceri

• Today's topic is hemoglobinopathies, important in international medicine
• Hemoglobin is a key protein complex that binds and transports oxygen
• Hemoglobinopathies are related to the structure of hemoglobin, a tetramer
• Tetramer stays fluid in plasma or cytoplasm, but individual globins precipitate if alone
• Hemoglobin consists of four globin chains and four heme groups
• Each heme group has protoporphyrin bound to ferrous iron that binds one oxygen molecule
• Each hemoglobin protein binds 4 oxygen molecules
• Two genetic loci control hemoglobin genes: chromosome 16 for alpha genes, chromosome 11 for beta genes
• Red blood cell production and globin gene use varies over time
• Alpha chain expression starts in the yolk sac, alpha genes are in use by the sixth week of prenatal age
• Beta genes usage is delayed, fetal chains used during fetal life, switches to transcription of adult beta genes after birth
• Most hemoglobin during gestation is hemoglobin F, which drops after delivery
• At six months, hemoglobin A predominates
• Problems with alpha chain are evident at birth
• Beta chain defects manifest after six months
• Clinical signs of beta thalassemia not evident at birth
• Most hemoglobinopathies defects are hereditary and can be asymptomatic, mild, severe, or lethal
• Classification ranges from qualitative defects to quantitative defects, hemoglobin variants, hereditary persistence of fetal hemoglobin and acquired hemoglobinopathies

Types of Hemoglobin Defects

• Qualitative defects involve structural issues like reduced solubility (e.g., sickle cell disease with HbS)
• Quantitative defects involve reduced globin chain synthesis
• Thalassemic syndromes are examples of quantitative defects
• Hemoglobin variants with thalassemic phenotype include Hb E and Hb Lepore
• Acquired hemoglobinopathies caused by meta-hemoglobinemia or carbon monoxide poisoning

Global Impact and Genetic Predispositions

• Hemoglobinopathies affect a significant percentage of the global population
• Hemoglobinopathies remains a top priority of organizations like WHO and the American Society for Hematology
• 270 million people are carriers of hemoglobinopathies
• Each year, there are 300,000 new affected births, 200,000 with sickle cell anemia and 65,000 with thalassemia
• Distribution varies, thalassemia common in Mediterranean, sickle cell mostly in Africa
• Heterozygous hemoglobin variants offer resistance to plasmodium, agent of malaria, but can cause hemoglobinopathies
• A balance in evolution exists between protection from malarial infections, and being exposed to genetic diseases
• Genetic recessive transmission involves both parents as carriers so prenatal diagnosis is important

Sickle Cell Disease

• It originates from a structural defect
• It is frequent in Africa, affecting 1/10 individuals of being a carrier
• This is the result of carrying one heterozygous mutation and substitution of hemoglobin A
• A mutation of glutamic acid is substituted with valine at position 6 of the beta globin gene
• The mutation causes hemoglobin to have low oxygen affinity, resulting in deoxygenation and sickling
• Deoxygenation and sickling results in red blood cells that alter morphology
• Increase in direct bilirubin, increase in LDH, increase in reticulocytes, jaundice and gallstones indicate sickling crises
• Homozygous individuals substitution of Hb S over the normal haemoglobin once a few months from birth have passed
• Sickle cell crisis occurs from stress such as infections, which can cause acidosis
• Cold weather can prompt vaso-occlusion
• Hot weather prompts dehydration

Clinical Manifestations: Vaso-occlusive Crisis

• Organs with small vessel circulation suffer from vaso-occlusion
• The fingers are affected, resulting in a sausage finger appearance due to swelling
• The infarct of the femoral head is the most extreme effect, resulting in necrosis
• Acute chest syndrome may occur, leading to pulmonary infarction.
• Patients will have pain so they try and compensate with hyperventilation
• Low oxygen tension may occur so the clinical picture will worsen, take out the pain to allow normal breathing
• Splenic infarcts from sickling crises can cause autosplenectomy

Managing Sickle Cell Crisis

• Analgesics are used to treat sickle cell crisis, use high doses of morphine
• Hydration and alkalization is useful, if there is any infection they may be treated with antibiotics
• Blood transfusions are used to reduce the amount of hemoglobin S

Stroke

• Strokes due to sickle cell are more common in children as ischemic, but adults develop hemorrhagic types
• There risk is higher with pain, which increases blood pressure, leading to hemorrhages
• Dactylitis, white blood cell counts, aenemia and use of Hb-F are indicators
• Hydroxyurea reduces the risk of paintful crisis with patients

Thalassemia: Genetic Mutations Leading to Anemia

• Alpha thalassemia results from missing alpha genes
• Beta thalassemia arises from beta gene defects
• Deletions or mutations may result in total lack of alpha or beta chains

Alpha Thalassemia: Gene Variations and Impact

• Four alpha genes exist, resulting in a spectrum of defects
• Defects range from mild (microcytosis) to fatal (death in utero)
• Missing all genes leads to hydrops fetalis and death

Beta Thalassemia: Prevalence and Phenotypes

• Beta thalassemia is frequent
• Beta genes cause decrease in protein production
• Heterozygous individuals are asymptomatic
• Homozygous are severe transfusion dependent anemia
• Excess alpha chains precipitate in red blood cells leading to erythtoptesis
• Ineffective erythropoiesis and the bone marrow produces non-effective red blood cells and the marrow inflames

Hemoglobin Timeline

• HBG to HBA occurs at 3-6 months, clinical manifests after
• Clinical manifestations come at the hemoglobin switch at 3-6 months of age and the symptoms occur

Beta Thalassemia Traits and Manifestations

• Beta 0 trait is a frameshift mutation can the
• Beta Plus is related to messenger
• Heterozygous individuals are microcytic
• Homozygous individuals come from compound heterozygosity
• Defects lead to precipitation of α chains, erythropoiesis, hemolysis, dacryocytes