Hemolytic Anemias

Type Type of Mutation/ Cause Pathogenesis Clinical picture and findings

hemolysis
Sickle cell Extravascular Point mutation in beta-globin chain-glu On deoxygenation-polymerizaton and reversible Homozygous: severe anemia, HCT 18-30%,
anemia hemolysis replaced by val- S Hb sickling, continued exposure-ireversible – reticulocytosis, hyper-bilirubinemia, crisis
Can be homozygous- all chains have mononuclear phagocytosis & microvascular Hetero: asymptomatic until exposure to severe
mutation or heterozygous- abt half obstructions. hypoxia
chains have mutation Hypospleenism in adults, spleenomegaly in
Particularly predisposed with salmonella children- infections.
osteomyelitis
Thalasemia intravascular α- thalasemia: 4 genes on ch 16 Excessive β- & γ- chains- form stable tetramers Major:
hemolysis deletions- 1- silent carries, 4- hydrops (Hb H, Hb bart) low damage, ineffective in O2 Microcytic hypochromic + poikilocytosis
fetalis, 3- disease delivery Failure of normal development
β- thalasemia: 2 genes on ch 11 Decrease in β-chains – decreased Hb Skeletal deformities, reticulocytosis.
point mutations on certain regions of More imp: increase in free α-chains that aggregate, Iron overload – leads to cardiac failure (need
gene: in promoter & unsplicing region form inclusion in RBC (reduce plasticity of RBC, iron chelators)
of intron- β+ (reduced β-chains) becomes more susceptible to mononuclear Minor
In exon & splicing region of intron- β0 phagocytosis) destruction also of blasts – Mild microcytic hypochromic
(absence of β-chains) ineffective erythropoisis - iron overload Normal life expectancy
G6PD Intra- & extra- G6PD gene on ch X forms G6PD Exposure to drugs, toxins or infections increases H No symptoms unless exposure oxidative injury.
deficiency vascular enzyme that regenerates GSH after its peroxide so increases oxidation of GSH to GSSG, In males severe oxidant injury
hemolysis oxidation GSH regeneration is impaired so – accum. of H In females asymptomatic
Mutation causes more rapid decay of peroxide which denatures Hb. This ppts causing Heinz bodies (precipitated Hb) and bite cells
enzyme (A- variant) IVhemolysis and also EVhemolysis in spleen (phagocytosis by splenic phagocytes)
Paroxysmal intravascular Acquired membrane defect secondary PIGA deficient BM cells are present in normal PIG-tailed proteins (3 that prevent activation of
nocturnal hemolysis to a mutation that involves myeloid individuals, when there is immune-mediated complement on normal RBC’s) cannot be
hemoglobinuria stem cells. Mutation in X-linked PIGA destruction or suppression of BM cells by expressed so RBC sensitive to lytic activity of
(synthesis of intramembranous recognition of sp. PIG-tailed antigens the PIGA complement, also not expressed on granulocytes
glycoprotein anchor – PIG) deficient cells do not express the targets and so and platelets – susceptibility to infections and
escape the attack and replace BM IVthrombosis
Immuno- Warm: IgG or (rarely) IgA active at 37 Opsonization by IgG and subsequent phagocytosis +ve direct/ indirect coombs test for both
hemolytic deg. 60% idiopathic and 40 % by splenic macrophages. Attempts of phagocytosis Chronic mild anemia with moderate
anemia underlying disease (SLE) or drugs (a- leads to injured bits of CM – decreased SA:V ratio spleenomegaly
methyl dopa, penicillin) – spheroidal cells – sequestration
Extravascular
Cold: IgM binds to CM below 30 deg. Complement most active at 37 deg. so no Acute during recovery from Mycoplasma
hemolysis
(in distal parts) IVhemolysis, when cells go to warmer regions pneumonia and infectious mononucleosis or
IgM is not well bound but leaves behind C3b chronic resulting in transient mild anemia with
opsonin causing phagocytosis by kupffer cells often Raynaud phenomenon
(EV)
Resulting from Intravascular Valve prostheses and microangiopathic Valves cause abnormal pressure gradient and Burr, hemlet and triangle cells
trauma hemolysis (caused by DIC, malignant HT, SLE or turbulent blood flow, and RBCs are squeezed thru
disseminated cancer) narrowed vessels, results in mechanical damage in
both
malaria Intravascular Plasmodium vivax, malariea, ovale & After infecting hepatocytes, merozites infect Spikes of shaking, chills and fever at intervals
hemolysis falciparum (most fatal causing cerebral erythrocytes forming trophozites (characteristic to which coincide with merozite release from RBC.
malaria and blackwater fever) each specie) which divides giving rise to new Brown discoloration of spleen, liver, lymph
merozites that destroy RBCs upon escape nodes & BM, massive spleenomegaly
(hyperplasia of mononuclear phagocytes)

Type Cause
Iron Deficiency Low dietary intake (rare),
malabsorption (e.g. gastrectomy),
increased demands (pregnancy,
infants), chronic blood loss (from
GIT – peptic ulcer, hemorrhoids -
or female genital tract)
Anemia of Occurs in chronic microbial
chronic disease infections (osteomyelitis,
bacterial endocarditis, lung
abcess), chronic immune
disorders (rheumatoid arthritis,
regional enteritis) and neoplasms
(Hodgkin, lung & breast cancer)
Megaloblastic Deficiency of folic acid from
anemia poor diet or increased metabolic
needs. Or inhibition of folate
metabolism by methotrexate,
acidic foods & beans, phenytoin.
pernicious anemia Impaired
absorption of vitamin B12 by:
*malabsorption (lack of vit B12
uncommon), *autoimmune
reaction against parietal cells or
IF,
*surgery and gut disorders
(gastrectomy regional enteritis)
or *aging (gastric atrophy &
achlohydria)
Aplastic Suppression of multipotent
myeloid stem cells caused by:
*idiopathic, *myelotoxic agents
(irradiation or myelotoxic druds),
*drugs and chemicals
(antineoplastic drugs, benzene,
chloramphenicol, or sensitivity to
sulfonamides, phenylbutazone
etc.), *viral infection
Myelophthisic Associated with metastasis
arising from breast, lung,
prostate or thyroid 1ry lesion or
with myelofibrosis
Anemias of Diminished Erythropoiesis
Pathogenesis
Starts with decline in serum ferretin and
stainable amounts of iron in BM. Followed
by decrease in circulating iron and rise in
transferrin iron-binding capacity – impact
on Hb, myoglobin and other iron
compounds. When more severe – impaired
work performance, brain function and
immunocompetence
Sequestration of iron from cells from the
storage compartment (mononuclear
phagocyte storage pool) and suppression of
erythropoiesis due to inflammatory
mediators (IL-1, TNF, interferon-alpha) that
are released from the underlying disease.
vit B12 required for regeneration of
tetrahydrofolate, Folic acid provides
tetrahydrofolate (carrier of a carbon group)
so both required for DNA synthesis.
Deficiency – delay in nuclear maturation
and cell division of erythroid precursors
producing megaloblasts (also granulocyte
precursors produce giant megakaryocytes)
some megaloblasts have very defective
DNA that they undergo apoptosis in BM,
others give mature RBC’s but output is
diminished. The enlarged RBCs are prone
to premature destruction by mononuclear
phagocyte system leading to accumulation
of iron (in mononuclear phagocytes)
Autoreactive T-cells (patients respond to
immunosuppressive therapy aimed at T
cells) where viral antigens, drug-drived
haptens and genetic damage create
neoantigens within stem cells that are
targets for autoreactive T cells
Bone marrow failure caused by extensive
replacement of BM by tumors or other
lesions
Clinical picture
Mostly asymptomatic with weakness
and pallor in severe cases. Long-term
severs anemia – thinning, flattening
and spooning of fingernails, pica,
increase in platelet count. Sometimes
develops plummer-vinson syndrome
__
Treatment:
erythropoietin administration may
improve but only treatment of
underlying condition is reliable
Non-specific symptoms relating to
pancytopenia (weakness, pallor, easy
fatigability, petechia, easy infection).
Alimentary tract related symptoms are
common e.g. sore tonge (rapid dividing
GIT cells). In vit B12 deficiency only
neurological symptoms may take place
e.g. symmetric numbness, tingling,
burning in feet or hands, unsteadiness
of gait, loss of position sense
*Cellular morphology: hypercellular
BM, nuclear-cytoplasmic asynchrony,
megaloblasts – delicate finely
reticulated nuclear chromatin,
megakaryocytes – bizarre multi-lobed
nulei
Symptoms relating to pancytopenia
(weakness pallor, dyspnea,
petechiae,frequent persistant minor
infections or sudden onset of chills or
fever)
Normocytic, normochromic,
sometimes slight macrocytic.
Reticulocytosis is absent
Spleenomegaly is absent
Anemia and thrombocytopenia
(pancytopenia)
Diagnosis
Low: Hb, HCT, MCV, serum
ferretin, iron levels, transferring
saturation, microcytic hypochromic
RBCs. HIGH total iron-binding
capacity
Normocytic normochromic, or
hypocytic hypochromic, low serum
iron, (similar to iron deficiency)
but: Increased storage iron in
marrow macrophages, increased
serum ferretin, decreased total iron-
binding capacity
Smear of peripheral blood and bone
marrow. To differentiate between
vit B12 – serum folate and vit B12
levels and RBC folate levels
Low serum vit B12 levels, normal
or elevated folate, histamine-fast
gastric achlohydria, anti IF
antibodies, megaloblastic anemia
findings, leucopenia, schilling test
(unable to absorb an oral dose of vit
B12 but when administered with IF
absorption takes place)
Differential diagnosis to
differentiate between it and
myelophthisic (or other
pancytopenias) – hypocellular BM
owing to stem cell failure
*Treatment: BM transplantation v.
effective in patients nontransfused
and younger than 40. other patients
– immunosuppressive therapy
Peripheral blood smear shows
immature RBCs (teardrops) ,
slightly elevated WBC count,
leukoerythroblastosis