Hemoglobinopathies Flashcards
definition of thalassemia
- genetically heterogenous condition resulting from imbalance between amounts of alpha and beta globin chains that are synthesized
thalassemias arise from
- mutations which partially or completely inactivate production of alpha or beta globin chains
inactivation of alpha chain is generally
- full deletion
inactivation of beta chain is generally
- point mutations
ways to classify thalassemias
- severity of clinical manifestations
- major hemoglobin species formed
- genotype
symptoms of thalassemia minor
- mild symptoms if any
symptoms of thalassemia major
- severe symptoms
- patients are transfusion dependent
symptoms of thalassemia intermedia
- between major and minor
- patients not transfusion dependent
B^0 thalassemia
- mutations cause absent beta globin synthesis
B+ thalassemia
- mutations cause decreased (but still present) beta globin synthesis
another name for beta thalassemia major
- Cooley’s anemia
genotype of beta thalassemia major
B^0/B^0
when does severe anemia develop in beta thalassemia major
- 2-12 months
- infants make gamma, delta, and alpha, not beta yet
beta thalassemia major seen in which population
- mediterraneans
beta thalassemia major diagnosis by
- hemoglobin electrophoresis showing alpha 4 tetramers
- absence of normal hemoglobin A
beta thalassemia major symptoms
- anemia
- splenomegaly - worsens due to sequestration
- bony deformities
- iron overload issues
iron overload issues
- bronze skin
- liver failure
- endocrine failure
instability of alpha tetramers leads to
- ineffective erythropoiesis
- destruction of produced RBCs
infective erythropoiesis example
- intramedullary hemolysis
intramedullary hemolysis
- hemolysis of RBC precursors inside marrow
anemia leads to
- increased epo production
- more ineffective erythropoiesis
bone deformities caused by
- marrow expansion
iron overload develops due to
- transfusions
- iron hyper absorption from gut
beta thalassemia minor (trait) genotype
- B+/B^0
beta thalassemia trait symptoms
- generally asymptomatic
- not so many alpha 4 tetramers
beta thalassemia trait MCV
- microcytic
- around 70
beta thalassemia trait anemic
- may or may not be
- mild if present
beta thalassemia trait RBC count
- very elevated
beta thalassemia trait RDW
- normal
- since all cells will be microcytic and hypochromic
beta thalassemia trait diagnosis by
- hemoglobin electrophoresis
beta thalassemia trait - hemoglobin electrophoresis in adults shows
in newborns
- unregulation of delta chains
- around 4-8% Hgb A2
not seen in newborns since species are predominantly HbF
alpha thalassemia one gene deletion symptoms
- typically silent
- maybe minimal microcytosis
alpha thalassemia one gene deletion anemia
- anemia not present
alpha thalassemia one gene deletion Hb electrophoresis result
- normal
alpha thalassemia two gene deletion symptoms
- mildly anemic
alpha thalassemia two gene deletion MCV
anemic?
- mildly microcytic
- MCV around 70
mildly anemic (Hg 10-11)
alpha thalassemia two gene deletion Hb electrophoresis in adults
- normal
alpha thalassemia two gene deletion Hb electrophoresis in newborns
- abnormal
- will make hemoglobin Barts (gamma 4)
alpha thalassemia two gene deletion seen in africans
- a-/a-
- trans deletion
alpha thalassemia two gene deletion seen in asians
- aa/–
- cis deletion
hemoglobin H disease genotype
- a-/–
- three gene deletion
hemoglobin H disease results
Hemoglobin H = Beta 4 tetramers
hemoglobin H (beta 4 tetramers) form
causes
- Heinz bodies
- causes bite cells and hemolytic anemia
hydrops fetalis genotype
–/–
hydrops fetalis result
- 4 gamma tetramers
- Hemoglobin barts
- no alpha chains form
hydrops fetalis in utero
- intrauterine death
hydrops fetalis treatment
- treated in utero
- exchange transfusions
hemoglobin S amino acid switch
- Glu 6 changed to Val 6
deoxy HbS compared to HbA
- less soluble
- polymerizes and forms long fibers
hemoglobin C amino acid switch
- Glu 6 to Lys 6
hemoglobin C result
- leads to increased cellular dehydration
hemoglobin C cells found
population targeted
- target cells
- hemoglobin c crystals
west African descent
HbS polymerizes and cell sickle in conditions under
- hypoxia
- acidosis
Leads to cellular dehydration
- multiple cycles of sickling and unsickling
cells in HbS eventually become
- irreversibly sickled
- obstruct small blood vessels
sickled and unsickled red cells suffer
- hemolysis
sickled cells and endothelial cells
- abnormal adhesion to endothelial cells
sickle cell disease genotype
- homozygous SS
S/B^0 thalassemia
- indistinguishable from SS
S/B+ thalassemia
- milder disease
- some normal beta chains are produced
the presence of HbC and HbS
- leads to more intracellular dehydration
- worsening sickling
if Hgb falls below patient’s baseline in sickle cell disease
- look for other causes
- Parvovirus B19
- splenic or hepatic sequestration
- acute chest syndrome
leukocytes and platelets in sickle cell disease
- leukocytosis - elevated WBC
- thrombocytosis - elevated platelets
spleen in SS adult patients
- functionally asplenic
- spleen has infarcted
cells seen in functionally asplenic patients
- Howell jolly bodies
sickle cell disease thromboses
- increased risk for venous clots
- risk present in sickle cell trait as well
sickle cell crises
- splenic sequestration crisis
- aplastic crisis
- painful (vaso-occlusive) crisis
splenic sequestration crisis in children
- rapid and extensive trapping of RBCs in spleen
splenic sequestration crisis symptoms
- profound anemia
- massive splenomegaly
- hypovolemic shock
- occurs quickly
which sickle cell crisis is most common
- painful (vaso-occlusive) crisis
painful crisis
how to treat
- periodic episodes of acute vascular occlusion
- treat pain
- supplemental O2
- folate replacement
- replace fluid
painful crisis usually affects
- bones and large joints
painful crisis triggers
- exercise
- dehydration
- infection
- cold
- stress
- menstruation
- surgery/trauma
- pregnancy
autospenectomy from sickle cell disease makes patient more susceptible to infections by
- infections by encapsulated organisms
sickle cell disease makes patient more susceptible to sepsis by
- encapsulated organisms
sickle cell disease infection by ______ if undergoing iron chelation therapy
- yersinia
- vibrio
sickle cell disease osteomyelitis and septic arthritis caused by
- salmonella osteomyelitis
respiratory complication of sickle cell disease
- acute chest syndrome
- pulmonary hypertension
most common cause of death in patients with sickle cell disease
- acute chest syndrome
acute chest syndrome definition symptoms
- hypoxemia
- new infiltrate on CXR
- new fever, chest pain, dyspnea, or cough
infections in acute chest syndrome usually with
- atypical organisms
- chlamydia and mycoplasma
acute chest syndrome etiologies
- fat embolism from necrotic bone marrow
- sequestration of sickled red cells
- pulmonary infarction
- hypoventiliation from rib infarct, narcotic administration
- pulmonary edema from fluid overload
treatment of acute chest syndrome
- antibiotics, oxygen
- simple transfusion to lower HbS concentration
pulmonary hypertension occurs in what fraction of SCD adults
- 1/3
median age of stroke in SCD patients
- 5 years old
stroke cause in SCD patients
- disordered blood vessels
- not due to atherosclerosis
acute treatment of stroke in SCD patients
- exchange transfusion
chronic treatment of stroke in SCD patients
- chronic regular transfusions
if transcranial dopplers show narrowing in the circle of Willis then chronic regular transfusions will prevent
- chronic regular transfusions prevent first instance of stroke
in an adult, one unit of blood raised Hb by
1
complications of transfusion in SCD
- iron overload
- allo-immunization
- leg ulcers
- renal
- AVN
- priapism
- proliferative retinopathy
organ damage associated with iron overload
- heart failure
- liver failure
- endocrine failure
treatment for iron overload
- chelation
how to avoid allo-immunization in AA
- transfuse blood negative for C, E, Kell blood groups
- reduce frequent transfusion in AA
treatment of sickle cell
- hydroxyurea
how hydroxyurea works
- increases amount of HbF
- decreases concentration of HbS
effects of hydroxyurea
- increases baseline hemoglobin values
- reduces number of sickle cell crises
- reduces episodes of acute chest syndrome
- prevent pulmonary hypertension
- reduces mortality
side effect of hydroxyurea
- bone marrow suppression
contraindications for hydroxyurea
- pregnancy
- poor/erratic followup
