Hemoglobinopathies Flashcards
Hemoglobinopathies vs. Normal
Normal adult Hb is composed of two alpha chains and two beta chains (α2β2)
Also contains small amount composed of two alpha chains and two delta chains (α2δ2)
Many Hemoglobin Variants Most are silent HbS HbC HbE – Most Common in Southeast Asia Thalassemia
Teleologically protective
Most are Heterozygous – because homozygous = death with severe symptoms
Hb Electrophoresis
Utilized method for the detection of hemoglobinopathies
Hb Biosynthesis
The biosynthesis of hemoglobin involves the coordinated synthesis of its two major components:
a) Heme b) Globin
Globins are polypeptide chains, the production of which, like all proteins, involves transcription followed by processing of mRNA transcripts and then ribosomal translation
Rate of globin production is modulated by a variety of cellular factors, notably heme
In normal subjects
Globin chain synthesis is tightly controlled where ratio of production of -globin chains and non -globin chains are balanced
Thalassemia
Spectrum of diseases characterized by reduced or absent production of one or more globin chains
The excess, unpaired globin tetramers become denatured and precipitate within the red cells, forming Heinz Bodies, and these inclusions result in accelerated red cell destruction
Each thalassemia syndrome is associated with small, poorly hemoglobinized red cells (i.e., microcytosis & hypochromia)
Alpha Thalassemia: Silent and Minor
Silent Carrier: SE Asia, 28% African Americans.
Normal or slightly decreased MCV with or without HbH inclusions
Alpha-thalassemia minor:
SE Asia, 3% of Black Americans, Mediterranean
No clinical disease
No or mild anemia, decreased MCV, target cells
HbH inclusions may be seen
Genetic counseling
Alpha Thalassemia: HbH
HbH disease
SE Asia, Mediterranean, Middle East
Formation of unstable beta4 (HbH), which precipitates so RBC’s removed by spleen (chronic hemolysis)
Life-long mild-moderate anemia (Hb 8-12 g/dl)
Decreased MCV, HbH inclusions+++
Normal life expectancy.
Alpha Thalassemia: Hydrops Fetalis
Barts Hydrops Fetalis
Almost exclusively in SE Asians
Only HbBarts (gamma4) is present; very high oxygen affinity
Lethal : Stillbirth or death within hours of birth
Beta Thalassemia
Due to impaired production of beta-globin chains
Excess alpha-globin chains are unstable
Incapable of forming soluble tetramers
They precipitate in the cell
Degree of alpha-globin chain excess determines severity of clinical manifestations
Profound in beta thalassemia major
Less pronounced in heterozygotes
Beta Thalassemia Minor
Heterozygotic with one normal beta globin allele and one beta globin thalassemic allele
Mediteranean
CBC with hypochromia and microcytosis
Total RBC elevated compared to Normal
Hgb usually > 10g/dL
MCV
Beta Thalassemia Major
Infants with severe beta-thal major are well at birth
Symptoms emerge during 2nd 6 months of life
Clinical expression of severe phenotype is heterogenous
Differences in mutations producing beta-thal lesion [e.g. beta (0) vs beta (+)]
Interactions that modify alpha globin inclusion burden (e.g. accompanying alpha thal)
Level of HbF
Probable impact of as yet unidentified modifying genes
Symptoms arise from level of anemia
Jaundice, chipmunk facies, liver and bladder, splenomegaly, kidneys
Beta Thalassemia Major: Endocrine, Cardiopulmonary, and Aplastic Crisis
Endocrine and metabolic abnormalities Hypogonadism Growth failure Diabetes Hypothyroidism
Cardiopulmonary complications
Heart failure and arrhythmias
Cardiac hemosiderosis = cardiomyopathy
Pulmonary hypertension
Aplastic crises – parvovirus B19
Beta Thalassemia Major: Lab Findings
Hypochromic, microcytic anemia
Increased WBC, normal platelet count
Iron studies - increased serum Fe, transferrin saturation and ferritin
Bone marrow – erythroid hyperplasia
Hemoglobin electrophoresis
Only HbF (increased) and HbA2 are present
Variable amounts of HbA if transfused
Beta Thalassemia Major: Tx
Chronic Hypertranfusion Therapy: if you transfuse a lot, you will need to chelation to prevent iron overload
Splenectomy is common to decrease amount of hemolysis
Bone marrow transplants are not widespread at this point
Folate Supplementation
Sickle Cell Anemia
Many will live with Hb of 6 because they have had it since infant and adapt to it
Micro-infarcts that are so painful, dehydrated, low O2 that had sickle crisis
Have HbS and HbF
Sickle Cell Anemia Complications
Autosplenectomy – by the time they are a teenager they won’t have a spleen anymore because it atrophies
Sepsis, priapism, MI, multi-organ failure, transfusion reactions
Renal injury over time causes low EPO
Jaundice, icteric sclera, bilirubin elevation
Iron deficiency, folate deficiency, hemolysis
Depression, anxiety disorders go along with sickle cell
Chronic pain syndromes need to be addressed
Sickle Cell Acute Vasooclusive Crises
Acute Vasoocclusive Crises
Degree of polymer formation/cellular damage
Interacting with other factors in the cells environment (endothelial cells and leukocytes)
Neutrophil transmigration
Dehydrated dense sickle cells contribute to anemia and hemolysis
Second source of nociceptive: tissue necrosis
Bone infarction of the spine and long bones, avascular necrosis, chronic leg ulcers, and splenic infarct
Sickle Cell: Sepsis and Infection
Wound infections from chronic skin ulcers, and must have wound debridement or treatments
Many have ports placed in lumbar vessels because vessels go over time because chronic IV access
Acute Chest Syndrome
A new pulmonary infiltrate in a clinically ill patient with sickle cell disease
Fever, cough, chest pain, tachypnea, wheezing, rales on exam
Pneumonia in usual host involves primarily the airspaces.
Pulmonary embolus involves primarily the blood vessels.
In SCD if there is a process which initially involves the airspaces and causes local hypoxia, such as pneumonia or atelectasis–then the blood vessels become involved with microvasular vaso-occlusion. So acute chest syndrome is probably a more appropriate term than pneumonia, even when infection is present because of the vasooclusion that accompanies infection, although to varying degrees.
Sickle Cell Tx
Hydroxyrea can cause leukemia after a while, but decreases pain, acute chest syndrome, blood transfusions, and hospitalization; results in increased HbF
Penicillin- prophylactic
Folic Acid
