PATHOLOGY OF MALARIA AND

HAEMOGLOBINOPATHIES
DR. A SALAMI
 LEARNING OBJECTIVES
• Students should have learnt about the
pathophysiology of malaria infection and
haemoglobinopathies
• Students should have learnt about the morphological
organ and microscopic changes
• Students should have learnt about major classes of
hamoglobinopathies
• Students should have learnt about the morphological
changes in haemoglobinopathy and interactions with
malarial infections.
 MALARIA
• An infectious disease caused by Plasmodium
species.
• Usually transmitted by the bite of the Anopheles
mosquitoe.
• There are four types of plasmodium responsible
for malaria which includes: P. falciparum, p.
vivax, P. ovale and P. malaria
• The illness caused by each species and the
predominant geographic location differs.
DISTRIBUTION OF MALARIA
 MALARIA – LIFE CYCLE
• The sporozoite is found in the mosquitoe.
• On entry into the blood within minutes it infects and multiplies
in hepatocytes using the thrombospondin and properdin
receptor.
• After about a week the hepatocytes rupture releasing the
merozoites that infect erythrocytes using sialic acid residues on
glycophorin molecule thus becoming trophozoites.
• The trophozoites transform into schizonts which multiply in the
erythrocytes and periodically rupture the host cell to release
many new merozoites.
• Each period of rupture coincides with the clinical chills and fever
experienced by the host.
 MALARIA - LIFE CYCLE

• Some of the
trophozoites form
gametocytes which
infect the mosquitoe.
• Hypnozoites are
formed in P. vivax and
P. ovale.
• The hypnozoites cause
relapses of the
infection.
MALARIA LIFE CYCLE
MALARIA RING FORMS AND GAMETE
 PATHOGENESIS OF MALARIA INFECTION
• The pathology of the infection is caused by several mechanisms:
 The rupture of red cells causes release of mediators that activate
macrophages and endothelial cells which release cytokines.
 This causes production of cell adhesion molecules and fever
(PfEMP1).
 The protein adheres to other receptors on the vessels including
ICAM 1, chondroitin sulphate in placentae and CD36.
 The adhesion molecules cause the sequestration of parasitized
red cells in blood vessels.
 There is plugging of vascular channels in the brain, heart, lungs
and kidneys.
PATHOGENESIS OF MALARIA INFECTION
• Cytokines also cause pulmonary oedema, shock
and DIC in severe cases.
• Anaemia caused by haemolysis and cytokines
that inhibit the bone marrow.
• Sequestration of parasitized red cells in the
spleen and liver causes hypertrophy and
enlargement of the organ.
• Intravascular haemolysis causes haemoglobinuric
nephrosis (Blackwater fever) and renal failure.
 MALARIA
• The most virulent of the species is P. falciparum and is
most prevalent in Africa.
• The virulence of P. falciparum is due to several factors:
 several organisms can infect one erythrocyte.
It can infect red cells of any age unlike p. vivax and
ovale which infects young and p. malariale which
infects old.
It causes production of membrane adhesion proteins
which causes clumping through ‘Rossette’ formation.
It stimulates production of cytokines particularly the
anaphylatoxins.
Characteristic P. falciparum  P. vivax  P. ovale  P. malariae 
Duration of 5.5 8 9 15
intrahepatic phase
(days)

Number of 30,000 10,000 15,000 15,000

merozoites released
per infected
hepatocyte

Duration of 48 48 50 ` 72
erythrocytic cycle
(hours)

Red cell preference Younger cells Reticulocytes Reticulocytes Older cells

(but can and cells up to
invade cells 2 weeks old
of all ages)
 MORPHOLOGY
• Organs, particularly spleen and liver, show a slatey
grey colour due to deposition of hemozoin pigments
in the tissues.
• In the lungs alveolar capillary wall damage with
oedema.
• Heart may show focal hypoxic lesions with mild
infiltration of the interstitium.
• The parasitized red cells and macrophages
accumulate in the intervillous space of the placentae.
• There is hypoxia and IUGR of the fetus.
 MORPHOLOGY
• Brain is swollen and oedematous with thromboses and
congestion of small vessels.
• There are focal areas of ring haemorrhages and focal
areas of microglial aggregation (Durck granulomas).
• Kidneys may show congestion with hemoglobin casts in
the blood vessels
• P. malariae particularly causes glomerular disease
(mesangioproliferative glomerulonephritis) while both P.
Malariae and P. falciparum can cause tubulointerstitial
damage.
• There may be haemoglobinuric acute tubular necrosis
and interstitial inflammation.
 MORPHOLOGY
• Hyperplasia of the macrophages in the spleen
and hepatocytes with hepatosplenomegally.
• The spleen is often massively enlarged with
hypersplenism (hyperactive malarial
splenomegally).
• Splenic rupture and fibrosis may result.
• There is usually dilation of the sinusoids and
there may be foci of extramedullary
hemopoiesis.
 MORPHOLOGY
• There is mild hepatic dysfunction with raised
hepatic enzymes.
• There may be mild jaundice with hepatomegally.
• The sinusoids are congested with parasitised
erythrocytes and hemozoin containing
hepatocytes.
• There is mild inflammation and there may be
centrilobular necrosis due to ischemia.
• There may also be fatty change and cholestasis.
BRAIN AND PLACENTAE
LIVER AND SPLEEN
 TYPES OF MALARIA
• Algid malaria – malaria with hypovolemic shock
• Bilious malaria – malaria with severe jaundice
• Dysenteric malaria – passage of bloody stools
• Choleric malaria – malaria with passage of
profuse loose stools
• Pre-eclamptic malaria – seen in pregnancy
HAEMOGLOBINOPATHIES
 INTRODUCTION
• The haemoglobin molecule is made up of a
tetramer of two globin chains linked with heme.
• The major globin chains in the adult are paired α
(141 amino acids) and paired β (146 amino acids).
• The heme molecule contains a fe2+ in the ferrous
state.
• Each heme molecule binds a single haemoglobin
molecule.
• The molecule is soluble but individual globin
chains are insoluble.
 HAEMOGLOBINOPATHY
• Haemoglobinopathies are disorders affecting the
structure, function or production of haemoglobin.
• They are often inherited as autosomal co-
dominant genes.
• They may present as haemolytic anemias,
erythrocytosis, cyanosis or vaso-occlusive lesions.
• Most are asymptomatic until 3 – 9 months (α
thallasemia are symptomatic in utero)
 CLASSES OF HAEMOGLOBINOPATHIES

• There are five classes:

• Structural haemoglobinopathies
• Thalassemia syndromes
• Thalassemic haemoglobin variants
• Hereditary persistence of fetal haemoglobin
• Acquired haemoglobinopathies
STRUCTURAL HAEMOGLOBINOPATHIES
STRUCTURAL HAEMOGLOBINOPATHIES
• Sickle cell syndrome is the prototype.
• Due to substitution of valine for glutamic acid in
the sixth amino acid of the β chain.
• Causes polymerization of the molecules at low
oxygen levels.
• The polymerization causes the formation of
fibrils (tactoids) that make the cell membrane
rigid and less deformable.
• There is occlusion of the microvasculature with
ischemia and infarction of tissues.
 PATHOGENESIS
• Sickle cell disease manifests as a result of
three main effects:
• 1 chronic extravascular haemolysis
• 2 microvascular occlusions with infarctions
• 3 tissue damage
• The sickled cells express adhesion molecules
which adhere to endothelium causing sluggish
flow of blood and hypoxia.
 MORPHOLOGY
• Bone – there is bone marrow expansion with bone
resorption. The bone marrow is hyperplastic and there
may be extramedullary haematopoiesis ( spleen and
liver).
• Blood – there is chronic anaemia with variable numbers
of sickled cells and increased reticulocyte count.
• Spleen – in childhood the spleen is enlarged with
congested sinusoids. By early adulthood the spleen
becomes fibrotic and shrunken due to repeated
infarctions (autosplenectomy). Histologically the fibrotic
spleen shows Gamna-Gandy bodies with siderophages,
calcium deposits and giant cells.
 MORPHOLOGY
• Brain – vascular occlusions in the brain occasionally
cause stroke like syndromes.
• Kidney – medullary ischemia with papillary necrosis.
This causes hyposthenuria due to impaired
glomerular filtration.
• Repeated infarctions can occur in other organs such
as the bones (aseptic necrosis), liver (sequestration
crises), retina (detachment and neovascularization),
skin (chronic ulcers), penis (priapism) and lungs (cor
pulmonale).
 THALASSEMIAS
• This genetic disorders result from defects in the
synthesis of one or more of the globin chains.
• This causes inadequate hemoglobin production and
imbalanced accumulation of the globin subunit.
• There is thus hypochromia and microcytosis with
ineffective haematopoiesis.
• They result from either total deletion or rearrangement
of the loci to point mutations that impair transcription,
processing, or translation of globin mRNA.
• The classification is based on the defective globin chain
and the degree of underproduction
Clinical Syndromes Genotype Clinical Features Molecular Genetics
β-THALASSEMIAS
β-Thalassemia Homozygous β-thalassemia Severe; requires blood Mainly point
major (β0/β0, β+/β+, β0/β+) transfusions mutations that lead
to defects in the
transcription,
β-Thalassemia Variable (β0/β+, β+/β+, β0/β, Severe but does not splicing, or
intermedia β+/β) require regular blood translation of β-
transfusions globin mRNA
β-Thalassemia Heterozygous β-thalassemia Asymptomatic with mild
minor (β0/β, β+/β) or absent anemia; red cell
abnormalities seen

α-THALASSEMIAS
Silent carrier -/α α/α Asymptomatic; no red cell Mainly gene
abnormality deletions
α-Thalassemia -/- α/α (Asian) Asymptomatic, like β-
trait -/α -/α (black African, Asian) thalassemia minor

HbH disease -/- -/α Severe; resembles β-

thalassemia intermedia

Hydrops fetalis -/- -/- Lethal in utero without

(Barts) transfusions
 PATHOGENESIS
• Defective beta globin chain leads to accumulation of
alpha chains in the erythrocyte which causes
membrane damage.
• Many erythrocyte precursors undergo apoptosis in the
marrow.
• Extravascular haemolysis also cause destruction of
others.
• There is extramedullary haemopoiesis in the spleen,
liver and lymph nodes with massive splenomegaly.
• There is enhanced iron absorption and storage with
secondary haemochromatosis causing multiple organ
failure.
THALLASEMIA FEATURES
 MORPHOLOGY
• Bone – skeletal abnormalities due to
osteoporosis and marrow expansion. There may
be irregular fusion of epiphyses with shortened
limbs. Pathological fractures can occur due to
bone thinning.
• Bone marrow – expansion with bone marrow
hyperplasia and bone cortical thinning.
• Blood- hypochromia and microcytosis with
target cells and inclusions within the
erythrocyte. Also show increased reticulocyte
count.
 MORPHOLOGY
• Growth – there is growth retardation and endocrine
dysfunction with delayed puberty.
• Liver and gall bladder – the liver is enlarged in
childhood due to extramedullary haematopoiesis.
Hemochromatosis also results in enlarged liver which
later causes fibrosis and cirrhosis. There is increased
gall stone formation.
• Spleen – there is massive splenomegaly due to
extramedullary haemopoiesis. There may be
associated hypersplenism
 MORPHOLOGY
• Heart – there is cardiac enlargement due to
chronic anaemia with resultant left ventricular
heart failure. Secondary haemochromatosis
also causes ventricular damage.
• Kidney – there is enlargement of the kidneys
due to extramedullary haemopoiesis. The renal
tubules are also dilated.
• Lungs – there are mild abnormalities in
pulmonary function.
 THALASSEMIC STRUCTURAL VARIANTS
• These are characterized by biosynthetic defect and
structural abnormality. They include:
• Hb Lepore (α2βδ) – the second globin is a product of
fusion by beta and delta genes and in some cases
gamma and beta chains (Hb Kenya).
• Homozygotes behaves clinically like beta thalassemia.
• Hb constant spring is an abnormally long alpha globin
chain due to disruption of the stop codon. It is usually
clinically mild.
 HEREDITARY PERSISTENCE OF FETAL
HAEMOGLOBIN
• Patients with this have abnormally high levels of
fetal haemoglobin.
• The HbF can be distributed within all the cells or
increased number of HbF cells.
• Usually asymptomatic but in homozygotes with all
the haemoglobin being HbF there is microcytosis
and hypochromia with raised hemoglobin levels.
• It results from deletion of beta and delta globin
genes.
 ACQUIRED HAEMOGLOBINOPATHIES
• This are often due to chemical reactions that affect the
functionality of the haemoglobin.
• Includes:
• Carbon monoxide poisoning which results in permanent
binding of carbon monoxide to haemoglobin.
• Methemoglobinemia in which ferrous iron is permanently
oxidized to a ferric state.
• This causes oxygen not to be released at the tissue level
with resulting cyanosis.
• Common drugs such as Phenacetin, Dapsone, Primaquine,
chloroquine, sulfanilamide e.t.c. can cause methemoglobin
 CONCLUSION
• Both haemoglobinopathies and malaria
infection act through the erythrocytic cells to
cause major organ system failure and
morphological changes.
• They are major causes of morbidity and
mortality in the tropics.