blood disorders affecting systemically and orally.

1. PATHOLOGY OF
BLOOD
Prepared by: Dr. Shaimaa
P.G student
Dept. of oral pathology

2. CONTENTS:
RED CELL DISORDERS
Anemia of Blood Loss: Hemorrhage
Hemolytic Anemias
Hereditary Spherocytosis
Sickle Cell Anemia
Thalassemia
Glucose-6-Phosphate Dehydrogenase Deficiency
Paroxysmal Nocturnal Hemoglobinuria
Immunohemolytic Anemias
Hemolytic Anemias Resulting from
Mechanical Trauma to Red Cells
Malaria
Anemias of Diminished Erythropoiesis:
Iron Deficiency Anemia
Anemia of Chronic Disease
Megaloblastic Anemias
Aplastic Anemia
Myelophthisic Anemia
Polycythemia

4. RED CELL DISORDERS
Disorders of red cells can result in anemia or, less commonly,
polycythemia (an increase in red cells also known as erythrocytosis).

5. Blood Loss
Acute: trauma
Chronic: gastrointestinal tract lesions, gynecologic disturbances
Increased Destruction (Hemolytic Anemias)
Intrinsic (Intracorpuscular) Abnormalities
Hereditary
Membrane abnormalities
Membrane skeleton proteins: spherocytosis, elliptocytosis
Membrane lipids: abetalipoproteinemia
Enzyme deficiencies
Enzymes of hexose monophosphate shunt: glucose-6-phosphate
dehydrogenase, glutathione synthetase
Glycolytic enzymes: pyruvate kinase, hexokinase
Disorders of hemoglobin synthesis
Structurally abnormal globin synthesis (hemoglobinopathies): sickle
cell anemia, unstable hemoglobins
Deficient globin synthesis: thalassemia syndromes
Acquired
Membrane defect: paroxysmal nocturnal hemoglobinuria

6. Extrinsic (Extracorpuscular) Abnormalities
Antibody-mediated
Isohemagglutinins: transfusion reactions, immune hydrops (Rh disease
of the newborn)
Autoantibodies: idiopathic (primary), drug-associated, systemic lupus
erythematosus
Mechanical trauma to red cells
Microangiopathic hemolytic anemias: thrombotic thrombocytopenic
purpura, disseminated intravascular coagulation
Defective cardiac valves
Infections: malaria

7. Impaired Red Cell Production
Disturbed proliferation and differentiation of stem cells: aplastic anemia,
pure red cell aplasia
Disturbed proliferation and maturation of erythroblasts
Defective DNA synthesis: deficiency or impaired utilization of
vitamin B12and folic acid (megaloblastic anemias)
Anemia of renal failure (erythropoietin deficiency)
Anemia of chronic disease (iron sequestration, relative
erythropoietin deficiency)
Anemia of endocrine disorders
Defective hemoglobin synthesis
Deficient heme synthesis: iron deficiency, sideroblastic
anemias
Deficient globin synthesis: thalassemias
Marrow replacement: primary hematopoietic neoplasms (acute leukemia,
myelodysplastic syndromes)
Marrow infiltration (myelophthisic anemia): metastatic neoplasms,
granulomatous disease

10. ANEMIA OF BLOOD LOSS: HEMORRHAGE
• acute blood loss exceeding 20% of blood volume. hypovolemic shock rather than
anemiahemodilution begins at once and achieves its full effect within 2 to 3 days
Recovery from blood loss anemia is enhanced by a compensatory rise in the
erythropoietin level, which stimulates increased red cell production and reticulocytosis
within a period of 5 to 7 days.
•chronic blood loss, iron stores are gradually depleted

11. HEMOLYTIC ANEMIAS
Anemias caused by accelerated red cell destruction are
termed hemolytic anemias. Destruction can be from intrinsic
(intracorpuscular) red cell defects, which are usually
inherited, or extrinsic (extracorpuscular) factors, which are
usually acquired.
Features shared by all uncomplicated hemolytic anemias
include
(1) a decreased red cell life span,
(2) a compensatory increase in erythropoiesis, and
(3) the retention of the products of degraded red cells
(including iron) by the body.

12. Hemolytic Anemias are associated with erythroid hyperplasia in the
marrow and increased numbers of reticulocytes in the peripheral
blood. In severe hemolytic anemias, extramedullary hematopoiesis
may appear in the liver, spleen, and lymph nodes.
Haptoglobin, a circulating protein that binds and clears free
hemoglobin, is completely depleted from the plasma, which also
usually contains high levels of lactate dehydrogenase(LDH) as a
consequence of its release from hemolyzed red cells in case of
intravascular hemolysis.

13. Hereditary Spherocytosis
This disorder stems from inherited (intrinsic) defects in the red
cell membrane that lead to the formation of spherocytes,
nondeformable cells that are highly vulnerable to
sequestration and destruction in the spleen. Hereditary
spherocytosis is usually transmitted as an autosomal dominant
trait; a more severe, autosomal recessive form of the disease
affects a small minority of patients.

14. A shared feature of the pathogenic mutations is that they
weaken the vertical interactions between the membrane
skeleton and the intrinsic membrane proteins. This defect
somehow destabilizes the lipid bilayer of the red cells, which
shed membrane vesicles into the circulation as they age.
Little cytoplasm is lost in the process and as a result the
surface area to volume ratio decreases progressively over
time until the cells become spherical.
PATHOGENESIS

15. Clinical Features
The characteristic clinical features are anemia, splenomegaly, and
jaundice.
•severe crises are triggered by parvovirus B19, which infects and
destroys erythroblasts in the bone marrow..
•Splenectomy provides relief for symptomatic patients by removing the
major site of red cell destruction.
•Partial splenectomy is gaining favor, because this approach may
produce hematologic improvement while maintaining protection
against sepsis.

16. MORPHOLOGY:

17. Sickle cell anemia
Sickle cell anemia is the most common familial hemolytic anemia in the
world.In parts of Africa where malaria is endemic, the gene frequency
approaches 30% as a result of a small but significant protective effect of
HbS against Plasmodium falciparum malaria. In the United States,
approximately 8% of blacks are heterozygous for HbS, and about 1 in
600 have sickle cell anemia.

18. PATHOGENESIS The three most important factors are:
•The presence of hemoglobins other
than HbS.
•The intracellular concentration of
HbS
•The transit time for red cells through
the microvasculature

19. •Two major consequences arise from the sickling of red cells.
•First, the red cell membrane damage and dehydration caused by
repeated episodes of sickling produce a chronic hemolytic anemia.The
mean life span of red cells in sickle cell anemia is only 20 days (one
sixth of normal).
•Second, red cell sickling produces widespread microvascular
obstructions, which result in ischemic tissue damage and pain crises.
Vaso-occlusion does not correlate with the number of irreversibly sickled
cells and therefore appears to result from factors such as infection,
inflammation, dehydration, and acidosis that enhance the sickling of
reversibly sickled cells.

20. MORPHOLOGY:
In peripheral smears, elongated, spindled, or boat-shaped irreversibly sickled red cells are
evident. Both the anemia and the vascular stasis lead to hypoxia-induced fatty changes in the
heart, liver, and renal tubules. There is a compensatory hyperplasia of erythroid progenitors in
the marrow.

23. Clinical Course: Gender predilection is controvertial.
•Homozygous sickle cell disease usually is asymptomatic until 6 months of age
when the shift from HbF to HbS is complete. From its onset, the disease runs an
unremitting course punctuated by sudden crises.
•The most serious of these are the vaso-occlusive,or pain, crises. he acute chest
syndrome and stroke are the two leading causes of ischemia-related death.
•A second acute event, aplastic crisis, is caused by a sudden decrease in red cell
production.
•patients with sickle cell disease are prone to infections.
•the marrow often causes bone resorption and secondary new bone formation, resulting
in prominent cheekbones and changes in the skull resembling a “crewcut” in
radiographs. Extramedullary hematopoiesis may appear in the liver and spleen.
•In children there is moderate splenomegaly (splenic weight up to 500 g) due to red
pulp congestion caused by entrapment of sickled red cells.
•Vascular congestion, thrombosis, and infarction can affect any organ

24. CREW CUT APPEARANCE OF SKULL
BONE

25. Oral manifestations:
Bone changes in dental radiographs consisting of mild to severe generalized osteoporosis and a
loss of trabeculation of the jaw bones with the appearance of large, irregular marrow spaces.
Changes in scrapings of oral epithelial cells showed nuclear enlargement, binucleation and an
atypical chromatin distribution.
Laboratory findings:
The red cell count may reach 1,000,000 cells or less per cubic millimetre with a
decreased haemoglobin level. On blood smear, typical sickle shaped red cell are seen.
Haemoglobin electrophoresis can be done to differentiate homozygous and
heterozygous.

26. Thalassemia
The thalassemias are inherited disorders caused by mutations that
decrease the synthesis of α- or β-globin chains. As a result, there is a
deficiency of Hb and additional red cell changes due to the relative
excess of the unaffected globin chain.

27. A diverse collection of α-globin and β-globin mutations underlies the thalassemias, which are
autosomal codominant conditions. As described previously, adult hemoglobin, or HbA, is a
tetramer composed of two α chains and two β chains. The α chains are encoded by two α-
globin genes, which lie in tandem on chromosome 11, while the βchains are encoded by a single
β-globin gene located on chromosome 16. The clinical features vary widely depending on the
specific combination of mutated alleles that are inherited by the patient. β-Thalassemia-The
mutations associated with β-thalassemia fall into two categories: (1) β0, in which no β-globin
chains are produced; and (2) β+, in which there is reduced (but detectable) β-globin synthesis.

30. In smears the red cells are small (microcytic) and pale (hypochromic), but regular in
shape. Often seen are target cells,cells with an increased surface area-to-volume
ratio that allows the cytoplasm to collect in a central, dark-red “puddle.” On the other
end of the spectrum, in β-thalassemia major, peripheral blood smears show marked
microcytosis,hypochromia, poikilocytosis (variation in cell size), and anisocytosis
(variation in cell shape). Nucleated red cells (normoblasts) are also seen that reflect
the underlying erythropoietic drive. β-Thalassemia intermedia and HbH disease are
associated with peripheral smear findings that lie between these two extremes.

32. Clinical Course
β-Thalassemia minor and α-thalassemia trait(caused by deletion of two α-globin
genes) are often asymptomatic. There is usually only a mild microcytic
hypochromic anemia;
generally, these patients have a normal life expectancy.
β-Thalassemia major manifests postnatally as HbF synthesis diminishes.
•Affected children suffer from growth retardation that commences in infancy.
•They are sustained by repeated blood transfusions,which improve the anemia and
reduce the skeletal deformities associated with excessive erythropoiesis.
• With transfusions alone, survival into the second or third decade is possible, but
systemic iron overload gradually develops owing to inappropriate uptake of iron from
the gut and the iron load in transfused red cells.
•Cachexia
•Hemosiderosis
•skeletal deformities

33. The child affected has yellowish pallor to the skin and has fever,
chills, malaise and a generalised weakness.
Splenomegaly and hepatomegaly
Face develops mongoloid features due to prominence of cheek
bones, protrusion or flaring of the maxillary anterior teeth, and the
depression of the bridge of the nose which gives rise to the
characteristic rodent facies.
Whereas thalassemia minor is generally without clinical
manifestations

34. •Lateral view of the skull reveals typical
thickening and widening of the cranial vault due
to marrow hyperplasia in the diploe.
• The outer table is displaced and ill defined and
there is a "hair-on-end" or sun ray appearance
due to vertical alignment of the coarse major
trabeculae.
• Even the upper portion of the occiput shares in
the generalized thickening of the cranial vault,
as well as the base of the skull and the anterior
fossa.
• There is marked hyperplasia of the facial
bones, maxillae and mandible, with virtual
obliteration of the paranasal sinuses and
mastoid sinuses.
•There is also a disproportionate overgrowth of
the upper maxilla with ventral and lateral
extension of the alveolar ridge producing
malocclusion of the jaws and a "rodent facies."

35. Thalassemia. Extramedullary hematopoiesis. Lobulated
soft tissue opacities are noted overlying the ribs
anteriorly and posteriorly.

36. Glucose-6-Phosphate Dehydrogenase Deficiency
Red cells are constantly exposed to both endogenous and
exogenous oxidants, which are normally inactivated by
reduced glutathione (GSH). Abnormalities affecting the
enzymes responsible for the synthesis of GSH leave red
cells vulnerable to oxidative injury and lead to hemolytic
anemias.
•G6PD gene is on the X chromosome
•most important variants is G6PD A-

37. •G6PD deficiency produces no symptoms until the patient is exposed
to an environmental factor (most commonly infectious agents or drugs)
that produces oxidants.
•The drugs incriminated include antimalarials (e.g., primaquine),
sulfonamides, nitrofurantoin, phenacetin, aspirin (in large doses), and
vitamin K derivatives.
•More commonly, episodes of hemolysis are triggered by infections,
which induce phagocytes to generate oxidants as part of the normal
host response.

38. •Oxidants, such as hydrogen peroxide, are normally sopped up by GSH, which is
converted to oxidized glutathione in the process.
•Because regeneration of GSH is impaired in G6PD-deficient cells, oxidants are free
to “attack” other red cell components including globin chains, which have
sulfhydryl groups that are susceptible to oxidation.
•Oxidized hemoglobin denatures and precipitates, forming intracellular inclusions
called Heinz bodies,which can damage the cell membrane sufficiently to cause
intravascular hemolysis.
•Other, less severely damaged cells lose their deformability and suffer further injury
when splenic phagocytes attempt to “pluck out” the Heinz bodies, creating so-
called bite cells. Such cells become trapped upon recirculation to the spleen and are
destroyed by phagocytes (extravascular hemolysis).

39. The complement system is a part of the immune system that enhances (complements)
the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is
part of the innate immune system,[1] which is not adaptable and does not change over
the course of an individual's lifetime. However, it can be recruited and brought into
action by the adaptive immune system.
•The complement system consists of a number of small proteins found in the blood, in
general synthesized by the liver, and normally circulating as inactive precursors
• When stimulated by one of several triggers, proteases in the system cleave specific
proteins to release cytokines and initiate an amplifying cascade of further cleavages.
The end result of this complement activation or complement fixation cascade is
massive amplification of the response and activation of the cell-killing membrane
attack complex. Over 30 proteins and protein fragments make up the complement
system, including serum proteins, serosal proteins, and cell membrane receptors. They
account for about 10% of the globulin fraction of blood serum and can serve
as opsonins.

41. Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder worthy of
mention because it is the only hemolytic anemia that results from an
acquired somatic mutation in myeloid stem cells.

42. Pathophysiology:
All cells have proteins attached to their membranes, often serving as a mode of communication or
signaling between the cell and the surrounding extracellular milieu. These signaling proteins are
physically attached to the cell membrane in various ways, commonly anchored by glycolipids
such as glycosyl phosphatidylinositols (GPI). PNH occurs as a result of a defect in the
assembling of these glycolipid-protein structures on the surface of blood cells.
The most common defective enzyme in PNH is phosphatidylinositol glycan A (PIGA), one of
several enzymes needed to make GPI.
A mutation in the PIGA gene can lead to the absence of GPI anchors expressed on the cell
membrane. When this mutation occurs in a hematopoietic stem cell in the bone marrow, all of
the cells it produces will also have the defect

43. Several of the proteins that anchor to GPI on the cell membrane are used
to protect the cell from destruction by the complement system, and,
without these anchors, the cells are more easily targeted by the
complement proteins.Although red blood cells, white blood cells and
platelets are targeted by complement, red blood cells are particularly
vulnerable to lysis

44. A small proportion of patients report attacks of abdominal pain, difficulty
swallowing and pain during swallowing, as well as erectile
dysfunction in men; this occurs mainly when the breakdown of red blood
cells is rapid, and is attributable to spasm of smooth muscle due to red
cell breakdown products.
Forty percent of people with PNH develop thrombosis (a blood clot) at
some point in their illness. This is the main cause of severe
complications and death in PNH

45. Immunohemolytic Anemias
Some individuals develop antibodies that recognize determinants on red
cell membranes and cause hemolytic anemia. These antibodies may
arise spontaneously or be induced by exogenous agents such as drugs
or chemicals.
Immunohemolytic anemias are uncommon and classified on the basis of
(1)the nature of the antibody and
(2) the presence of predisposing conditions

46. The diagnosis of immunohemolytic anemias depends on the
detection of antibodies and/or complement on red cells.
This is done with the direct Coombs antiglobulin test,in
which the patient’s red cells are incubated with antibodies
against human immunoglobulin or complement. In a positive
test result, these antibodies cause the patient’s red cells to
clump (agglutinate). The indirect Coombs test,which assesses
the ability of the patient’s serum to agglutinate test red cells
bearing defined surface determinants, can then be used to
characterize the target of the antibody

48. Hemolytic Anemias Resulting from Mechanical
Trauma to Red Cells
Abnormal mechanical forces result in red cell hemolysis in
a variety of circumstances. Traumatic hemolysis can occur
incidentally during any activity involving repeated physical blows or
their equivalent (e.g., marathon racing, karate
chopping, bongo drumming) but is of little clinical importance. More
significant mechanical hemolysis is sometimes produced by defective
cardiac valve prostheses (the blender effect), which can create
sufficiently turbulent blood flow to shear red cells. Microangiopathic
hemolytic anemia is observed in pathologic states

49. Other causes of microangiopathic hemolytic anemia include
malignant hypertension, systemic lupus erythematosus, thrombotic
thrombocytopenic purpura, hemolytic uremic
syndrome, and disseminated cancer. The morphologic alterations in
the injured red cells (schistocytes) are striking and quite characteristic;
“burr cells,” “helmet cells,” and “triangle cells” may be seen

50. Malaria
It is estimated that malaria affects 500 million and
killsmore than 1 million people per year, making it one of the
most widespread afflictions of humans. Malaria is endemic in
Asia and Africa, but with widespread jet travel cases are now
seen all over the world.
It is caused by one of four types of protozoa. Of these, the
most important is Plasmodium falciparum, which causes
tertian malaria (falciparum malaria), a serious disorder with a
high fatality rate. The other three species of Plasmodium that
infect humans—Plasmodium malariae, Plasmodium vivax,
and Plasmodium ovale—cause relatively benign disease. All
forms are transmitted by the bite of female Anopheles
mosquitoes, and humans are the only natural reservoir.

52. Clinical Features
The distinctive clinical and anatomic features of malaria are related
to the following factors:
• Showers of new merozoites are released from the red cells at
intervals of approximately 48 hours for P. vivax, P. ovale,and P.
falciparumand 72 hours for P. malariae. The episodic shaking, chills, and
fever coincide with this release.
• The parasites destroy large numbers of infected red cells, thereby
causing a hemolytic anemia.
• A characteristic brown malarial pigment derived from hemoglobin
called hematin is released from the ruptured red cells and produces
discoloration of the spleen, liver, lymph nodes, and bone marrow.
• Activation of defense mechanisms in the host leads to a marked
hyperplasia of mononuclear phagocytes, producing massive
splenomegaly and occasional hepatomegaly

53. ANEMIAS OF DIMINISHED ERYTHROPOIESIS
The category of anemias involving diminished
erythropoiesis includes anemias that are caused by an
inadequate dietary supply of nutrients, particularly iron, folic
acid, and vitamin B12. Other anemias of this type are those
associated with bone marrow failure (aplastic anemia),
systemic inflammation (anemia of chronic disease), or bone
marrow infiltration by tumor or inflammatory cells
(myelophthisic anemia).

54. Iron deficiency anemia
Iron deficiency arises in a variety of settings:
•Chronic blood loss -gastrointestinal tract (e.g., peptic ulcers, colonic
cancer, hemorrhoids) and the female genital tract (e.g., menorrhagia,
metrorrhagia, cancers).
•vegetarian diets
•Increased demands-infancy and pregnancy
•Malabsorption can occur with celiac disease or after gastrectomy

56. Iron stores are depleted first, marked by a decline in
serum ferritin and the absence of stainable iron in the bone
marrow.
These changes are followed by a decrease in serum iron and a
rise in the serum transferrin.
Ultimately, the capacity to synthesize hemoglobin,
myoglobin, and other ironcontaining proteins is
diminished, leading to microcytic anemia, impaired work
and cognitive performance, and even reduced
immunocompetence.

57. Diagnostic criteria include anemia,
hypochromic and microcytic red cell indices,
low serum ferritin and iron levels,
low transferrin saturation,
Increased total iron-binding capacity, and,
ultimately, response to iron therapy.

58. Plummer-Vinson or Paterson-Kelly syndrome presents as a classical triad of dysphagia, iron-
deficiency anemia and esophageal webs.
•the syndrome is extremely rare
•middle-aged women, in the fourth to seventh decade of life but the syndrome has also been
described in children and adolescents.
•Clinical picture:
•The dysphagia is usually painless and intermittent or progressive over years, limited to solids
and sometimes associated with weight loss.
•weakness, pallor, fatigue, tachycardia
•glossitis, angular cheilitis and koilonychia
•Enlargement of the spleen and thyroid
•most important clinical aspects of Plummer-Vinson syndrome is the association with upper
alimentary tract cancers

59. Eitiology:
The most important possible etiological factor is iron deficiency. Other possible factors include
malnutrition, genetic predisposition or autoimmune processes.
•Since Plummer-Vinson syndrome is associated with an increased risk of squamous cell
carcinoma of the pharynx and the esophagus, the patients should be followed closely.

60. Anemia of Chronic Disease
Anemia associated with chronic disease is the most
common form of anemia in hospitalized patients. It
superficially resembles the anemia of iron deficiency but
arises instead from the suppression of erythropoiesis by
systemic inflammation. It occurs in a variety of disorders
associated with sustained inflammation, including:
• Chronic microbial infections, such as osteomyelitis,
bacterial endocarditis, and lung abscess
• Chronic immune disorders, such as rheumatoid arthritis
and regional enteritis
• Neoplasms, such as Hodgkin lymphoma and carcinomas
of the lung and breast

61. PATHOGENESIS
The anemia of chronic disease stems from high levels of
plasma hepcidin,which blocks the transfer of iron to erythroid
precursors by downregulating ferroportin in macrophages. The
elevated hepcidin levels are caused by pro-inflammatory
cytokines such as IL-6, which increase hepatic hepcidin
synthesis. In addition, chronic inflammation blunts
erythropoietin synthesis by the kidney, lowering red cell
production by the marrow. The functional advantages of these
adaptations in the face of systemic inflammation are
unclear; they may serve to inhibit the growth of
irondependent microorganisms or to augment certain aspects
of host immunity.

62. Clinical Features
•As in anemia of iron deficiency, the serum iron levels usually are
low in the anemia of chronic disease, and the red cells may even be
slightly hypochromic and microcytic.
•Unlike iron deficiency anemia, however, storage iron in the bone
marrow is increased, the serum ferritin concentration is elevated, and
the total iron-binding capacity is reduced.
•Administration of erythropoietin and iron can improve the anemia, but
only effective treatment of the underlying condition is curative.

63. Megaloblastic Anemias
The two principal causes of megaloblastic anemia are folate
deficiency and vitamin B12 deficiency. Both vitamins
are required for DNA synthesis and the effects of their
deficiency on hematopoiesis are essentially identical.

64. Pathogenesis:
Many megaloblasts are so defective in DNA
synthesis that they undergo apoptosis in the marrow
(ineffective hematopoiesis). Others mature into red
cells but do so after fewer cell divisions, further
diminishing the output of red cells. Granulocyte and
platelet precursors are also affected (although not as
severely) and most patients present with
pancytopenia (anemia, thrombocytopenia, and
granulocytopenia).

67. Patients may have a sore tongue and canker sores.
A spectrum of mental changes, from a change in personality to
psychosis, as well as peripheral neuropathy, can occur in both folate and
cobalamin deficiencies. Peripheral neuropathy presents as numbness,
pain, tingling, and burning in a patient’s hands and feet. Patients may
report loss of sensation and that they feel like they are wearing a thin
stocking or glove.

68. Folate (Folic Acid) Deficiency Anemia
The risk of clinically significant folate deficiency is high in those with a
poor diet (the economically deprived, the indigent, and the elderly) or
increased metabolic needs (pregnant women and patients with chronic
hemolytic anemias).
•Folate is present in nearly all foods but is destroyed by 10 to 15 minutes
of cooking. Thus, the best sources are fresh uncooked vegetables and
fruits.
•Food folates are predominantly in polyglutamate form and must be split
into monoglutamates for absorption, a conversion that is hampered by
concurrent consumption of acidic foods and substances found in beans
and other legumes.

69. •Phenytoin (dilantin) and a few other drugs also inhibit folate
absorption, while others, such as methotrexate, inhibit folate
metabolism.
•The principal site of intestinal absorption is the upper third of the small
intestine; thus, malabsorptive disorders that affect this level of the gut,
such as celiac disease and tropical sprue, can impair folate uptake.

70. Clinical features:
Vitamin B12 deficiency can also cause a demyelinating disorder of the peripheral
nerves and the spinal cord. There are many causes of vitamin B12deficiency.
The term pernicious anemia,a relic of days when the cause and therapy of this
condition were unknown, applies to vitamin B12 deficiency that results from defects
involving intrinsic factor.

71. onset of the anemia of folate deficiency is insidious, being
associated with nonspecific symptoms such as weakness and easy
fatigability.
Vitamin B12 deficiency can also cause a demyelinating disorder of
the peripheral nerves and the spinal cord.

72. Intrinsic factor plays a critical role in the absorption of vitamin
B12, a multistep process that proceeds as follows:
1. Peptic digestion releases dietary vitamin B12, allowing it to bind a
salivary protein called haptocorrin.
2. On entering the duodenum, haptocorrin–B12complexes are processed
by pancreatic proteases; this releases B12, which attaches to intrinsic
factor secreted from the parietal cells of the gastric fundic mucosa.
3. The intrinsic factor–B12 complexes pass to the distal ileum and
attach to cubulin, a receptor for intrinsic factor, and are taken up into
enterocytes.
4. The absorbed vitamin B12 is transferred across the basolateral
membranes of enterocytes to plasma transcobalamin, which delivers
vitamin B12 to the liver and other cells of the body.

73. Pernicious anemia/ Addisonian anemia/ Biermer anemia/ Hunter-
Addison anemia/ Lederer anemia/ Biermer-Ehrlich anemia/Addison-
Biermer anemia
It is the most frequent cause of vitamin B12 deficiency.This disease
seems to stem from an autoimmune reaction against parietal cells and
intrinsic factor itself, which produces gastric mucosal atrophy.
•an autoimmune disorder with a genetic predisposition and the disease is
associated with human leucocyte antigen (HLA) types A2, A3, and B7
and A blood group. Antiparietal cell antibodies occur in 90% of patients
with pernicious anemia

74. Three types of antibodies have been found:
parietal canalicular antibodies, which bind to the mucosal parietal
cells;
blocking antibodies, which disrupt the binding of vitamin B12 to
intrinsic factor;
and intrinsic factor–B12complex antibodies, which prevent the complex
from binding to cubulin.

75. • Pernicious anemia frequently occurs concomitantly with other
autoimmune diseases, such as Hashimoto thyroiditis, Addison disease,
type 1 diabetes mellitus and acquired agammaglobulinemia.
•Chronic vitamin B12 malabsorption is also seen after gastrectomy
(owing to loss of intrinsic factor–producing cells) or ileal resection
(owing to loss of intrinsic factor–B12complex–absorbing cells),
•and in disorders that disrupt the function of the distal ileum (such as
Crohn disease, tropical sprue, and Whipple disease).
•Particularly in older persons, gastric atrophy and achlorhydria may
interfere with the production of acid and pepsin, which are needed to
release the vitamin B12 from its bound form in food.

76. Clinical Features
Pernicious anemia is rare before the age of 30 years and increases in
frequency with advancing age.
The disease is often characterized by the presence of a triad of
symptoms:
generalized weakness,
a sore, painful tongue,
and numbness or tingling of the extremities.

77. stiffness and difficulty in walking, general irritability, depression or
drowsiness as well as incoordination and loss of vibratory sensation.
the degeneration of posterior and lateral tracts of the spinal cord with
loss of nerve fibers and degeneration of myelin sheaths. Degeneration of
the peripheral nerves also occurs.

78. In some cases the lingual manifestations are the first sign of the disease.
tongue is ‘beefy red’ in color, either in
entirety or in patches scattered over the
dorsum and lateral borders. small and
shallow ulcers — resembling aphthous
ulcers — occur on the tongue.
Characteristically, with the glossitis,
glossodynia and glossopyrosis, there is
gradual atrophy of the papillae of the
tongue that eventuate in a smooth or
‘bald’ tongue which is often referred to
as Hunter’s glossitis or Moeller’s
glossitis and is similar to the ‘bald
tongue of Sandwith’ seen in pellagra. the
inflammation and burning sensation
extend to involve the entire oral mucosa
but, more frequently, the rest of the oral
mucosa exhibits only the pale yellowish
tinge noted on the skin.

79. Laboratory findings:
The red blood cell count is seriously decreased, often to 1,000,000 or less
per cubic millimeter. Poikilocytosis is seen in peripheral smear. The
hemoglobin content of the red cells is increased but the mean corpuscular
hemoglobin concentration is normal. Leukocytes reduced in number, but
are increased in average size, innumber of lobes to the nucleus
(becoming the so-called macropolycytes) and anisopoikilocytosis. Mild
to moderate thrombocytopenia is noticed. Coexistent iron deficiency is
common because achlorhydria prevents solubilization of dietary ferric
iron from foodstuffs. Striking reticulocyte response and improvement in
hematocrit values after parenteral administration of cobalamin is
characteristic.

80. Serum. The indirect bilirubin may be elevated because pernicious
anemia is a hemolytic disorder associated with increased turnover of
bilirubin. The serum lactic dehydrogenase usually is markedly increased.
The serum potassium, cholesterol, and skeletal alkaline phosphatase
often are decreased. Serum antibodies for IF are highly specific.
Bone marrow. hypercellular and show trilineage differentiation.
Erythroid precursors are large and often oval. The nucleus is large and
contains coarse chromatin clumps, providing a checkerboard appearance.

81. History findings to help identify a cobalamin deficiency are as follows:
•Evidence for achlorhydria such as abdominal discomfort, reflux, early
satiety, and abdominal bloating: This condition can impair cobalamin
absorption.
•Pernicious anemia: These patients may have signs of other autoimmune
disorders such as thyroid disorders, type I diabetes, or Addison disease.
•Family history, HLA (HLAA2, A3, B7, B12), and type A blood
(Scandinavians and African Americans)
•History of a gastrectomy
Conditions that affect the terminal ileum (site of cobalamin absorption),
such as inflammatory bowel disease, sprue, or ileal resection
•Conditions in which cobalamin is competitively consumed: History of
abdominal surgery might suggest a blind loop syndrome. Exposure to
raw fish might suggest D latuminfestation.
•Zollinger-Ellison syndrome or pancreatic insufficiency: There is
impaired binding of cobalamin to intrinsic factor.

82. •Strict vegetarian with no consumption of eggs and dairy products
•A history of folate administration without vitamin B-12 therapy: This
should alert one to the possibility of the progression of neuropsychiatric
complications in a patient who is not anemic.
•A history of megaloblastosis since childhood: This would suggest a
hereditary cause of cobalamin deficiency.

83. History findings to help identify folate deficiency are as follows:
•Poor nutrition, alternative diets, and excessive heating and dilution of
foods
•Chronic alcoholism
•Conditions that interfere with folate absorption, including inflammatory
bowel disease, sprue or gluten sensitivity, and amyloidosis
•Conditions that increase folate consumption, such as pregnancy,
lactation, hemolytic anemia, hyperthyroidism, and exfoliative dermatitis
•Hyperalimentation and hemodialysis
•Medications that affect folate
•Hereditary disorder: A lifelong history of megaloblastosis or folate
deficiency would suggest a hereditary disorder as the cause.

84. Aplastic Anemia
Aplastic anemia is a bone marrow failure syndrome characterized by
peripheral pancytopenia and general lack of bone marrow activity. It may
affect not only the red blood cells but also the white cells and platelets,
resulting in a pancytopenia. Paul Ehrlich, introduced the concept of
aplastic anemia in 1888 when he studied the case of a pregnant woman
who died of bone marrow failure. However, it was not until 1904 when
this disorder was termed aplastic anemia by Chauffard.

85. Primary aplastic anemia is a disease of unknown etiology which occurs
most frequently in young adults, develops rapidly and usually terminates
fatally. A disease known as Fanconi’s syndrome consists of congenital,
and sometimes familial, aplastic anemia associated with a variety of
other congenital defects including bone abnormalities, microcephaly,
hypogenitalism and a generalized olive-brown pigmentation of the skin.
Secondary aplastic anemia, on the other hand, is of known etiology,
occurs at any age and presents a better prognosis, particularly if the cause
is removed. The etiology of this secondary anemia is the exposure of the
patient to various drugs or chemical substances or to radiant energy in
the form of X-rays, radium or radioactive isotopes.

86. Drugs such as cetophenetidine, amidopyrine, organic arsenicals,
particularly sulfarsphenamine, benzol, chloramphenicol, qui nacrine
hydrochloride (Atabrine), trinitrotoluene, dinitrophenol, colloidal silver,
bismuth, mercury, sulfonamides and penicillin, although many others
have also produced the disease. On few occasions aplastic anemia is
preceded by infection by hepatitis viruses, Epstein-Barr virus (EBV),
HIV, parvovirus, and mycobacterial infections.

88. Pathophysiology of acquired aplastic anemia. The figure stresses the crucial and
related roles of the hematopoietic stem-cell compartment as a target for the immune
response. An inciting event, such as a virus or medical drug, provokes an aberrant
immune response, triggering oligoclonal expansion of cytotoxic T cells that destroy
hematopoietic stem cells (left panel, Onset). Bone marrow transplantation or
immunosuppressive therapy leads to complete response (CR) or partial response (PR)
by eradicating or suppressing pathogenic T-cell clones (middle panel, Recovery).
Relapse occurs with recurrence of the immune response, and the immunologically
stressed and depleted stem-cell compartment also allows selection of abnormal
hematopoietic clones that manifest as paroxysmal nocturnal hemoglobinuria,
myelodysplasia (MDS), and occasionally acute myelogenous leukemia (AML)

89. Clinical Course
Aplastic anemia affects persons of all ages and both sexes. The slowly
progressive anemia causes the insidious development of weakness,
pallor, and dyspnea.
Thrombocytopenia often manifests with petechiae and ecchymoses.
Granulocytopenia may be manifested by frequent and persistent minor
infections or by the sudden onset of chills, fever, and prostration
Aplastic anemia does not cause splenomegaly; if it is present, another
diagnosis should be sought. Typically, the red cells are normochromic
and normocytic or slightly macrocytic. Reticulocytes are reduced in
number (reticulocytopenia).

90. Oral Manifestations.
Petechiae purpuric spots or frank hematomas of the oral mucosa may
occur at any site, while hemorrhage into the oral cavity, especially
spontaneous gingival hemorrhage, is present in some cases. Such
findings are related to the blood platelet deficiency. As a result of the
neutropenia there is a generalized lack of resistance to infection, and this
is manifested by the development of ulcerative lesions of the oral mucosa
or pharynx. These may be extremely severe and may result in a condition
resembling gangrene because of the lack of inflammatory cell response.

91. Laboratory Findings.
The red blood cell count is as low as 1,000,000 cells per cubic
millimeter, with a corresponding reduction in the hematocrit and
hemoglobin levels. The thrombocytopenia results in a prolonged
bleeding time; the clotting time remains normal. Clot retraction is poor
and the tourniquet test is positive. The degree of cytopenia is useful in
assessing the severity of aplastic anemia. The presence of teardrop
poikilocytes and leucoerythroblastic changes suggest marrow aplasia
from infiltrative and dysplastic causes

92. Bone marrow smears the marrow appears normal or even hyperplastic.
In pancytopenia there is hypoplasia of all marrow elements. In cases of
less severe damage, moderate numbers of primitive cells persist. In
severe cases, hypocellular bone marrow with fatty replacement and
relatively increased nonhematopoietic elements such as plasma cells and
mast cells may be found. Hemoglobin electrophoresis and blood group
testing may show elevated fetal hemoglobin and red cell 1 antigen
suggesting stress erythropoiesis, which is observed in both aplastic
anemia and myelodysplastic syndromes.

93. POLYCYTHEMIA
Polycythemia, or erythrocytosis,denotes an increase in red cells per unit
volume of peripheral blood, usually in association with an increase in
hemoglobin concentration. Three forms of disease are recognized:
relative polycythemia,
primary polycythemia or erythremia ( polycythemia rubra vera) of
unkown etiology and
secondary polycythemia or erythrocytosis, due to some known stimulus.

94. Relative polycythemia is an apparent increase in the number of
circulating red blood cells that occurs as a result of loss of blood fluid
with hemoconcentration of cells, and is seen in cases of excessive loss of
body fluids such as chronic vomiting, diarrhea, or loss of electrolytes
with accompanying loss of water. This increase in the number of red
blood cells is only relative to the total blood volume, and therefore, is not
a true polycythemia.

95. Primary polycythemia, or polycythemia rubra vera, is characterized by a
true idiopathic increase in the number of circulating red blood cells and
of the hemoglobin level. It is characterized by bone marrow with an
inherent increased proliferative activity.

96. Secondary polycythemia the etiology is known. Secondary polycythemia
is caused due to absolute increase in red blood cell mass resultant to
enhanced stimulation of red blood cell production. In general, the
stimulus responsible for producing a secondary polycythemia is either
bone marrow anoxia or production of an erythropoietic stimulating
factor.

97. Bone marrow anoxia may occur in numerous situations such as
pulmonary dysfunction, heart disease, habitation at high altitudes or
chronic carbon monoxide poisoning.
Erythro poietic stimulatory factors include a variety of drugs and
chemicals such as coal-tar derivatives, gum shellac, phosphorus, and
various metals such as manganese, mercury, iron, bismuth, arsenic and
cobalt. Some types of tumors such as certain brain tumors, liver and
kidney carcinomas and the uterine myoma have also been reported
associated with polycythemia.
The mechanism for increased production of the red blood cells by these
tumors is unknown, but has been postulated as due to elaboration of a
specific factor which stimulates erythropoiesis.

98. Polycythemia Vera (Polycythemia rubra vera, erythremia, Vaquez’s
disease, Osler’s
disease)
Polycythemia vera (PV) is a chronic stem cell disorder with an insidious
onset characterized as a panhyperplastic, malignant, and neoplastic
marrow disorder. The most prominent feature is an absolute increase in
the number of circulating red blood cells and in the total blood volume
because of uncontrolled redblood cell production. This is accompanied
by increased white blood cell (myeloid) and platelet (megakaryocytic)
production, which is due to an abnormal clone of the hematopoietic stem
cells with increased sensitivity to the different growth factors for
maturation

99. Clinical Features.
Polycythemia vera often manifests itself primarily by headache or
dizziness, weakness and lassitude, tinnitus, visual disturbances, mental
confusion, slurring of the speech and inability to concentrate. The skin is
flushed or diffusely reddened, as a result of capillary engorgement and
high red cell mass, as though the patient were continuously blushing. the
digits may be cyanotic. Increased red blood cell mass increases blood
viscosity and decreases tissue perfusion, and also predisposes for
thrombosis.
Splenomegaly
Gastric complaints such as gas pains, belching and peptic ulcers are
common
Pruritus results from increased histamine levels released from increased
basophils and mast cells

100. Oral Manifestations.
The oral mucous membranes appear
deep purplish red, the gingiva and
tongue being most prominently
affected.
The cyanosis is due to the presence
of reduced hemoglobin in amounts
exceeding 5 gm/dl.
The gingivae are often engorged
and swollen and bleed upon the
slightest provocation.
Submucosal petechiae are also
common, as well as ecchymoses
and hematomas.
Intercurrent infection may occur,
but this is not related directly to the
disease

101. Laboratory Findings.
•Red blood cell mass and plasma volume can be measured directly using
radiochromiumlabeled red blood cells which show an increase in mass
with a normal or slightly decreased plasma volume.
•The red blood cell count is elevated and may even exceed 10,000,000
cells per cubic millimeter
•Because of the great
number of cells present,
both the specific gravity
and the viscosity of the
blood are increased.
•Leukocytosis is usual, as
is a great increase in the
number of platelets
(400,000–800,000/dl)

102. To be continued….