Page 560 - TNFlipTest

H20 Hematology
Hemolytic Anemia Toronto Notes 2019
Blood flow slows
sickle cells 􏰁H+
Hb S 􏰁CO2 polymers
Impaction Infarction
Figure 8. Pathophysiology of sickling
Functional asplenism: increased susceptibility to infection by encapsulated organisms
• S. pneumoniae
• N. meningitidis
• H. influenza
• Salmonella (osteomyelitis)
Treatment
• lifelongregulartransfusionstosuppressendogenouserythropoiesis
• ironchelation(e.g.deferoxamine,deferasirox,anddeferiprone)topreventironoverloadinorgansand
the formation of free radicals (which promote tissue damage and fibrosis)
• folicacidsupplementationifnottransfused
• allogeneicbonemarrowtransplantation(potentiallycurative)orcordbloodtransplant
• splenectomy(nowperformedlessfrequently)
β-Thalassemia Intermedia
Definition
• clinicaldiagnosisinpatientswhoseclinicalmanifestationsaretoomildtobeclassifiedasthalassemia major, but too severe to be classified as thalassemia minor
Clinical Features
• widevarietyofclinicalphenotypes
• inmostcasesofthalassemiaintermedia,bothβ-globingenesaffected
• threemainmechanismsaccountforthemilderphenotypecomparedtothalassemiamajor:(1)
subnormal (vs. absent) β-chain synthesis, (2) increased number of γ chains, (3) coinheritance of α
thalassemia (in some cases)
• complicationsmorecommonlyseeninthalassemiaintermediathanthalassemiamajorinclude
extramedullary hematopoiesis, leg ulcers, gallstones, thrombosis, pulmonary hypertension, and growth retardation
α-Thalassemia
Definition
• defect(s)inαgenes
• similargeographicdistributionasβ-thalassemia,buthigherfrequencyamongAsiansandAfricans
Clinical Features
• 1defectiveαgene(aa/a-):clinicallysilent;normalHb,normalMCV
• 2defectiveαgenes(cis:aa/--ortrans:a-/a-):decreasedMCV,normalHb
■ N.B. cis 2-gene deletion more common in Asia vs. trans 2-gene deletion more common in Africa – this leads to increased risk of fetal hydrops in offspring of Asian patients vs. African patients
• 3defectiveαgenes(a-/--):HbH(β4)disease;presentsinadults,decreasedMCV,decreasedHb,and splenomegaly
• 4defectiveαgenes(--/--):HbBarts(γ4)disease(hydropsfetalis);usuallyincompatiblewithlife
Investigations
• peripheralbloodfilm–screenforHbHinclusionbodieswithsupravitalstain
• electrophoresiscanbeusedtoidentifyHgHdisease,definitivediagnosiswithDNAgenotyping
Treatment
• dependsondegreeofanemia,referralforgenetic/prenatalcounselling
■ 1 or 2 defective α genes: no treatment required
■ HbH disease: similar to β-thalassemia intermedia
■ HbBarts: no definitive treatment, majority of pregnancies terminated (fetal/maternal mortality risk),
and intrauterine transfusion, stem cell transplants
Sickle Cell Disease
Definition
􏰁 blood viscosity
􏰀 pO2 Distorted RBC Deoxy HB S
•
•
autosomal recessive sickling disorders arise due to a mutant β-globin chain, most commonly caused by a Glu → Val substitution at position 6 (chromosome 11) resulting in HbS variant, rather than HbA (normal adult Hb)
■ increased incidence of HbS allele with Sub-Saharan African, Indian, Middle Eastern or Mediterranean heritage (thought to be protective against malaria)
sickle cell disease occurs when an individual has two HbS genes (homozygous, HbSS) or one HbS gene + another mutant β-globin gene (compound heterozygote) – most commonly HbS-β-thal and HbSC disease
Pathophysiology
• atlowpO2,deoxyHbSpolymerizesleadingtorigidcrystal-likerodsthatdistortmembranes→‘sickles’ • the pO2 level at which sickling occurs is related to the percentage of HbS present
• sicklingaggravatedbyacidemia,increasedCO2,increased2,3-DPG,fever,andosmolality
• fragilesicklecellsthencauseinjuryintwomainways
1. fragile sickle cells hemolyze (nitric oxide depletion)
2. occlusion of small vessels (hypoxia, ischemia-reperfusion injury)