A seminar on common blood disorders.

1. Hematologic Disorders And Immune
Deficiencies
SHASHI KIRAN
18/12/18
1

2. Contents
Introduction
Normal physiology of blood
Neutrophil disorders
Leukemia
Anemia
Thrombocytopenia
Antibody deficiency disorders
Conclusion
2

3. Introduction
3

4. Red blood cells
4-5.5 million cells per microlitre
Produced in bone marrow
120 days- destroyed in spleen
Iron containing haemoglobin pigment (12-16grams/dl)
Functions
1. Transport of oxygen from lungs to tissues
2. Transport of CO2 from tissues to lungs
3. Buffering action in blood
4. Blood group determination
4

5. White blood cells
5

6. Platelets
Platelets or thrombocytes- small colourless non nucleated bodies
1.5-4 lacs/cumm, lifespan-10 days
Functions
Role in blood clotting
Role in clot retraction
Role in hemostasis
Role in repair of ruptured blood vessel
Role in defense mechanism
6

7. All blood cells play an essential role in the maintenance of a healthy periodontium.
White blood cells (WBCs)- inflammatory reactions, cellular defense against microorganisms as
well as for pro-inflammatory cytokine release.
Red blood cells (RBCs)- gas exchange and nutrient supply to the periodontal tissues
Platelets- and they are necessary for normal hemostasis, recruitment of cells during
inflammation and wound healing.
Consequently, disorders of any blood cells or blood-forming organs can have a profound effect
on the periodontium.
7

8. 8
Abnormal bleeding from the gingiva or other areas of the oral mucosa
that is difficult to control is an important clinical sign that suggests a
hematologic disorder.
Petechiae and ecchymosis observed most often in the soft palate
area, are signs of an underlying bleeding disorder.
It is essential to diagnose the specific etiology to appropriately
address any bleeding or immunologic disorder.

9. 9
Deficiencies in the host immune response may lead to severely destructive periodontal
lesions.
These deficiencies may be primary (inherited) or secondary (acquired) and may be caused by
either immunosuppressive drug therapy or the pathologic destruction of the lymphoid system.
This seminar discusses common hematologic and certain immunodeficiency disorders that are
not related to the human immunodeficiency virus or acquired immunodeficiency syndrome

10. Neutrophil Disorders
Disorders that affect the production or function of leukocytes may result in severe periodontal
destruction.
PMNs (i.e., neutrophils) in particular play a critical role in bacterial infections, because PMNs are
the first line of defense.
A quantitative deficiency of leukocytes is typically associated with a more generalized periodontal
destruction that affects all teeth
Neutropenia
Agranulocytosis
lazy leukocyte syndrome, chediak higashi syndrome, Papillon-Lefe`vre syndrome, chronic
granulomatous disease, leukocyte adhesion deficiency.
10

11. Neutropenia
Neutropenia is a blood disorder that results in low levels of circulating neutrophils.
It is a serious condition that may be caused by diseases, medications, chemicals, infections, idiopathic
conditions, or hereditary disorders.
It may be chronic or cyclic and severe or benign. It affects as many as one in three patients who are
receiving chemotherapy for cancer.
ANC of 1000 to 1500 cells/µL is diagnostic for mild neutropenia.
ANC of 500 to 1000 cells/µL is considered moderate neutropenia
ANC of less than 500 indicates severe neutropenia.
11

12. Agranulocytosis
Agranulocytosis is a more severe neutropenia that involves not only neutrophils but also basophils
and eosinophils. It is defined as an ANC of less than 100
It is characterized by a reduction in the number of circulating granulocytes- severe infections,
including ulcerative necrotizing lesions of the oral mucosa, the skin, and the gastrointestinal and
genitourinary tracts.
Agranulocytosis has been reported after the administration of drugs such as aminopyrine,
barbiturates and their derivatives, benzene ring derivatives, sulfonamides, gold salts, and arsenical
agents.
It generally occurs as an acute disease. It may be chronic or periodic, with recurring neutropenic
cycles (e.g., cyclic neutropenia)
12

13. 13
The absence of a notable inflammatory reaction caused by a lack of granulocytes is a striking
feature.
The gingival margin may or may not be involved. With cyclic neutropenia, the gingival changes
recur with recurrent exacerbation of the disease. The occurrence of generalized aggressive
periodontitis has been described in patients with cyclic neutropenia
The onset of disease is
accompanied by fever,
malaise, general weakness,
and sore throat.
Ulceration in the oral
cavity, the oropharynx, and
the throat
The mucosa- isolated necrotic patches
that are black and gray and that are
sharply demarcated from the adjacent
uninvolved areas.
Gingival hemorrhage, necrosis,
increased salivation, and fetid
odor are accompanying clinical
features.

14. 14
Because infection is a common feature of agranulocytosis, the differential diagnosis involves
consideration of such conditions as necrotizing ulcerative gingivitis, noma, acute necrotizing
inflammation of the tonsils, and diphtheria.
Definitive diagnosis depends on the hematologic findings of pronounced leukopenia and the
almost complete absence of neutrophils.

15. Lazy leukocyte syndrome
an extremely rare disorder that manifests in both quantitative and qualitative neutrophil defects
characterized by recurrent infections due to both a deficiency in neutrophil chemotaxis and a
systemic neutropenia,
while the phagocytic function of the neutrophil remains intact
Within the bone marrow, the quantity and morphology of the neutrophils are normal.
Peripherally, however, there exists not only a severe neutropenia but also functional defects of
neutrophils with regard to chemotaxis
15

16. Constantopoulous et al. described a 5-month-old boy that presented with a high
fever, cough, bilateral pneumonia, oral stomatitis and purulent skin abscesses.
A similar case report is that of a 4-year-old diagnosed with lazy leukocyte
syndrome and followed over 7 years. The boy suffered from painful stomatitis,
gingivitis and recurrent ulcerations of the buccal mucosa and tongue.
Periodontitis progressed to the point of advanced alveolar bone loss and tooth
loss by the age of 7
16

17. Chediak-Higashi syndrome
Chediak-Higashi syndrome is a rare autosomal recessive
disorder that primarily affects neutrophils. (Altered
migration, degranulation and phagocytosis secondary to
intracellular megabodies- giant dysmorphic granules)
Its genetic etiology manifests itself early in life in the
form of partial oculocutaneous albinism, photophobia,
frequent pyogenic infections and lymphadenopathy.
17

18. Oral findings include severe gingivitis, ulcerations of the tongue and buccal mucosa, and early
onset periodontitis leading to premature loss of both deciduous and permanent dentitions
18

19. Papillon-Lefe`vre syndrome
Papillon-Lefe`vre syndrome is a rare autosomal recessive disease with a prevalence of one to
three cases per million in the general population
is described as a diffuse palmoplantar keratosis associated with aggressive periodontitis of
both primary and permanent dentitions.
deficits in chemotaxis, phagocytosis, and intracellular killing
19

20. The two essential features of Papillon-Lefe`vre syndrome are hyperkeratosis of the palms and
soles (either diffuse or localized) and generalized rapid destruction of the periodontal
attachment apparatus resulting in premature loss of both primary and permanent teeth
20

21. Leukocyte adhesion deficiency
LAD is a disorder that involves a deficiency in three membrane
integrins. CD18/C11a (LFA-1) CD18/CD11b, CD18/C11c.
The deficiency of these integrins prevents the neutrophil from
adhering to the vessel wall at the site of an infection.
Therefore, in spite of a leukocytosis (20,000–80,000 cells/ml),
neutrophils are unable to migrate into the affected tissues. The
clinical appearance is one of ulceration and necrosis of tissue,
but without signs of purulence
Delayed umbilical cord separation, persistent infections in
absence of purulence, severe periodontitis, fiery-red mucosa
21

22. Chronic granulomatous disease
Chronic granulomatous disease is an extremely rare clinical syndrome
characterized by life-threatening Staphylococcus, Proteus or
Pseudomonas species infections, hypergammaglobulinemia, and
widespread chronic granulomatous infiltrations
caused by congenital defects in the enzyme NADPH oxidase. The
defect prevents free oxygen radicals from being produced, and the
neutrophil’s inability to kill intracellular organisms predisposes
patients to recurrent bacterial and fungal infections
Recurrent bacterial and fungal infections, lymphadentitis; skin
abscesses, gingivitis/periodontitis
22

23. Leukemia
The leukemias are malignant neoplasias of WBC precursors that are characterized by the
following:
According to the cell type involved, leukemias are classified as lymphocytic or myelogenous. A
subgroup of the myelogenous leukemias are the monocytic leukemias
The term lymphocytic indicates that the malignant change occurs in cells that normally form
lymphocytes.
The term myelogenous indicates that the malignant change occurs in cells that normally form
red blood cells (RBCs), some types of WBCs, and platelets
23
(1) diffuse replacement of the
bone marrow with proliferating
leukemic cells;
(2) abnormal numbers and
forms of immature WBCs in the
circulating blood;
(3) widespread infiltrates in the
liver, spleen, lymph nodes, and
other body sites.

24. According to their evolution, leukemias can be acute (which is rapidly fatal), subacute, or
chronic
In acute leukemia, the primitive blast cells released into the peripheral circulation are immature
and non-functional
In chronic leukemia, the abnormal cells tend to be more mature and to have normal
morphologic characteristics and functions when released into the circulation
24
All leukemias tend to displace normal
components of the bone marrow elements
with leukemic cells, thereby resulting in the
reduced production of normal RBCs, WBCs,
and platelets
ANEMIA
THROMBOCYTOPENIA
LEUKOPENIA

25. Anemia results in poor tissue oxygenation, which makes tissues more friable and susceptible to
breakdown.
Leukopenia in the circulation leads to a poor cellular defense and an increased susceptibility to
infections.
Thrombocytopenia leads to bleeding tendency, which can occur in any tissue but which in
particular affects the oral cavity, especially the gingival sulcus
25

26. The Periodontium in Leukemic Patients
Leukemic Infiltration
Leukemic cells can infiltrate the gingiva and, less frequently, the alveolar bone. Gingival
infiltration often results in leukemic gingival enlargement
A study of 1076 adult patients with leukemia showed that 3.6% of the patients with teeth had leukemic
gingival proliferative lesions, with the highest incidence seen in patients with acute monocytic leukemia
(66.7%), followed by those with acute myelocytic– monocytic leukemia (18.7%) and acute myelocytic
leukemia (3.7%)
Leukemic gingival enlargement is not found in edentulous patients or in patients with chronic
leukemia, suggesting that it represents the accumulation of immature leukemic blast cells in the
gingiva adjacent to tooth surfaces with bacterial plaque.
26

27. Leukemic gingival enlargement consists of a basic infiltration of the
gingival corium by leukemic cells that increases the gingival
thickness and
creates gingival pockets in which bacterial plaque accumulates,
thereby initiating a secondary inflammatory lesion that contributes
to the enlargement of the gingiva.
It may be localized to the interdental papilla area or it may expand to
include the marginal gingiva and partially cover the crowns of the
teeth.
27

28. Clinically, the gingiva appears bluish red and cyanotic, with a rounding and tenseness of the
gingival margin.
The abnormal accumulation of leukemic cells in the dermal and subcutaneous connective tissue
is called leukemia cutis, and it forms elevated and flat macules and papules
28

29. Histology
Microscopically, the gingiva exhibits a dense, diffuse infiltration of predominantly
immature leukocytes in the attached and marginal gingiva. The normal connective
tissue components of the gingiva are displaced by the leukemic cells
The blood vessels are distended and contain predominantly leukemic cells, and the
RBCs are reduced in number. The epithelium shows a variety of changes, and it may
be thinned or hyperplastic.
Common findings include degeneration associated with intercellular and
intracellular edema and leukocytic infiltration with diminished surface
keratinization.
29

30. Scattered foci of plasma cells and lymphocytes with edema and degeneration
are common findings. The inner aspect of the marginal gingiva is usually
ulcerated, and marginal necrosis with pseudomembrane formation may also be
seen
The periodontal ligament may be infiltrated with mature and immature
leukocytes.
The marrow of the alveolar bone exhibits a variety of changes, such as localized
areas of necrosis, thrombosis of the blood vessels, infiltration with mature and
immature leukocytes, occasional RBCs, and the replacement of the fatty
marrow with fibrous tissue
30

31. Bleeding
Gingival hemorrhage is a common finding in leukemic patients even in
the absence of clinically detectable gingivitis.
Bleeding gingiva can be an early sign of leukemia. It is caused by the
thrombocytopenia that results from the replacement of bone marrow
cells with leukemic cells
This bleeding tendency can also manifest in the skin and throughout
the oral mucosa, where petechiae are often found, with or without
leukemic infiltrates. A more diffuse submucosal bleeding manifests as
ecchymosis.
31

32. Oral bleeding has been reported as a presenting sign in 17.7% of patients with acute leukemia
and in 4.4% of patients with chronic leukemia.
Bleeding may also be a side effect of the chemotherapeutic agents used to treat leukemia
32

33. Oral ulceration and infection
Granulocytopenia (diminished WBC count)- which increases the
host susceptibility to opportunistic microorganisms and leads to
ulcerations and infections.
Discrete, punched-out ulcers that penetrate deeply into the
submucosa and are covered by a firmly attached white slough can
be found on the oral mucosa.
Patients with a history of herpes virus infection may develop
recurrent herpetic oral ulcers (often in multiple sites) and large
atypical forms, especially after chemotherapy is instituted
33

34. Acute gingivitis and lesions that resemble necrotizing ulcerative
gingivitis are more frequent and more severe in patients with
terminal cases of acute leukemia
The gingiva is a peculiar bluish red, it is spongelike and friable,
and it bleeds persistently on the slightest provocation or even
spontaneously in leukemic patients.
This greatly altered and degenerated tissue is extremely
susceptible to bacterial infection, which can be so severe as to
cause acute gingival necrosis with pseudomembrane formation or
bone exposure
34

35. These are secondary oral changes that are superimposed on the
oral tissues that have been altered by the blood dyscrasia.
They produce associated disturbances such as systemic toxic effects,
loss of appetite, nausea, blood loss from persistent gingival
bleeding, and constant gnawing pain
Eliminating or reducing local factors (e.g., bacterial plaque) can
minimize the severe oral changes associated with leukemia.
In some patients with severe acute leukemia, symptoms may be
relieved only by treatment that leads to the remission of the
disease.
35

36. Anemia
Anemia is a deficiency in the quantity or quality of the blood as manifested by a reduction in
the number of erythrocytes and in the amount of haemoglobin
Anemia may be the result of blood loss, defective blood formation, or increased RBC
destruction.
Anemias are classified according to cellular morphology and hemoglobin content as follows:
(1) macrocytic hyperchromic anemia (pernicious anemia);
(2) microcytic hypochromic anemia (iron deficiency anemia);
(3) sickle cell anemia;
(4) normocytic–normochromic anemia (hemolytic or aplastic anemia).
36

37. Iron deficiency anemia
Iron deficiency anemia is the most common hematological disorder.
37

38. It may manifest in the orofacial region as atrophic glossitis, mucosal pallor and angular cheilitis.
Angular stomatitis (painful fissures at the corners of the mouth) and cheilosis (dry scaling of the
lips and corners of the mouth) are also common findings associated with iron deficiency anemia.
38

39. The Plummer–Vinson syndrome
This is otherwise called the Patterson–Brown–Kelly syndrome or sideropenic dysphagia. It is a
symptom complex caused by iron deficiency.
This syndrome manifests as atrophic glossitis, or angular cheilitis, and, occasionally,
hyperkeratotic lesions are seen in the oral mucosa.
It is also associated with koilonychias (or spoon nails), pagophagia and dysphagia due to
pharyngo esophageal ulcerations and esophageal webs
39

40. Pernicious anemia
Megaloblastic anemia
This may be caused by a vitamin B12 deficiency (commonly from pernicious anemia, surgical
resection of the ileum or small intestinal diverticula) or by a folic acid deficiency (most
commonly from malnutrition)
The oral manifestations- painful atrophy of the entire oral mucous membranes and tongue
(glossitis), stomatitis as well as mucosal ulceration (recurrent aphthous ulcers) in vitamin B12
and folate deficiency have long been recognized
40

41. These oral changes may occur in the absence of symptomatic anemia or of macrocytosis.
"Magenta tongue," which is said to be rather characteristic, may herald a B12 deficiency
41

42. Sickle cell anemia
Sickle cell disease is generically used to describe a group of disorders
characterized by the production of abnormal hemoglobin S (HBS)
The hallmark features of sickle cell disease are chronic hemolytic anemia and
vaso-occlusion resulting in ischemic tissue injury
Orofacial changes in HbSS as reported in the literature include midfacial
overgrowth attributable to marrow hyperplasia, increased thickening of the
skull and osteoporotic changes,
mandibular infarction that may be followed by osteosclerosis, osteomyelitis
of the mandible, anesthesia or paraesthesia of the mental nerve,
asymptomatic pulpal necrosis, orofacial pain, enamel hypomineralization
and diastema.
42

43. These dentofacial deformities are radiographically
characterized by a step-ladder appearance of the
alveolar bone and areas of decreased densities and
coarse trabecular pattern most easily seen between the
root apices of the teeth and the inferior border of the
mandible
Saint Clair de Velasquez and Rivera reported, in a study, that
the most common soft tissue oral manifestation of sickle cell
anemia in a Venezuelan population was buccal mucosa pallor,
while the most common hard tissue finding was enlarged
medullary spaces
43

44. Aplastic anemia
44
Aplastic anemia is due to the suppression of red
bone marrow
The onset is insidious and the clinical features
are due to reduction or complete absence of
erythrocytes, granulocytes and platelets

45. The most common orofacial manifestation of the disease is multiple hemorrhages, which most
often develop in patients with platelet counts less than 25,000/cumm
Oral and facial petechiae, gingival hyperplasia, spontaneous gingival bleeding, oral
hemorrhagic bullae, oral candidiasis, herpetic lesions
45

46. Thalassemia
These are a group of inherited hemolytic anemia involving defects in the synthesis of either the
α or the β polypeptide chains of hemoglobin(α-thalassaemia, β-thalassaemia)
The heterozygous form of the disease (thalassaemia minor) is mild and usually
asymptomatic,the only manifestation being hypochromic microcytic anemia.
Homozygous β-thalassaemia, also known as Cooley'sanemia or Mediterranean anemia, exhibits
the most severe clinical symptoms with marked orofacial deformities. The onset of symptoms
occurs early in infancy and the patients are severely anemic and have a short life expectancy
46

47. The most common orofacial manifestations are due to intense compensatory hyperplasia of the
marrow and expansion of the marrow cavity and a facial appearance known as "chipmunk"
face: enlargement of the maxilla, bossing of the skull and prominent malar eminences
47

48. 48

49. Thrombocytopenia
Thrombocytopenia is a term that is used to describe the condition of a reduced platelet count
that results from either a lack of platelet production or an increased loss of platelets
49

50. Purpura refers to the purplish appearance of the skin or mucous
membranes where bleeding has occurred as a result of decreased
platelets
Thrombocytopenic purpura may be idiopathic or it may occur
secondary to some known etiologic factor that is responsible for a
reduced amount of functioning marrow and a resultant reduction in
the number of circulating platelets.
(aplasia of the marrow, displacement of the megakaryocytes in the
marrow (as with leukemia), replacement of the marrow by tumor, and
destruction of the marrow by irradiation or radium or by drugs such as
benzene, aminopyrine, or arsenical agents)
50

51. Thrombocytopenic purpura is characterized by a low platelet
count, a prolonged clot retraction and bleeding time, and a
normal or slightly prolonged clotting time.
There is spontaneous bleeding into the skin or from the mucous
membranes. Petechiae and hemorrhagic vesicles occur in the oral
cavity, particularly in the palate, the tonsillar pillars, and the buccal
mucosa.
51

52. The gingivae are swollen, soft, and friable. Bleeding occurs
spontaneously or with the slightest provocation, and it is
difficult to control.
Gingival changes represent an abnormal response to local
irritation. The severity of the gingival condition is dramatically
alleviated by removal of the local factors
52

53. Antibody Deficiency Disorders
Agammaglobulinemia, or hypogammaglobulinemia, is an immune deficiency that results from
inadequate antibody production caused by a deficiency in B cells.
It can be congenital (X-linked or Bruton agammaglobulinemia) or acquired (common variable
immunodeficiency).
Congenital agammaglobulinemia is caused by an X-linked, recessive gene (Bruton tyrosine
kinase). It affects approximately 1 of every 100,000 individuals (only males have the disease)
53
The gene is responsible for B-cell
development. In the absence of
mature B cells, patients lack lymphoid
tissue and fail to develop plasma cells.
Thus, the production of antibodies is deficient.
Germinal centers where B cells proliferate and
differentiate are poorly developed in all
lymphoid tissues. The tonsils, adenoids, and
peripheral lymph nodes are small or absent.
.

54. Acquired or late-onset agammaglobulinemia is most often known as Common variable
immunodeficiency disease (CVID).
The disorder is characterized by the onset of recurrent bacterial infections during the second and
third decades of life as a result of drastic decreases in immunoglobulin and antibody levels
The basic immunologic defect of CVID is the failure of B-lymphocyte differentiation into plasma
cells.
54

55. In contrast to patients with the X-linked form of the disease, patients with CVID typically have an
enlarged spleen and swollen glands or lymph nodes.
Unlike the X-linked earlyonset form of the disease, CVID is not genetically determined (both
males and females are susceptible)
55

56. T-cell function remains normal in individuals with
agammaglobulinemia. The disease, whether congenital or
acquired, is characterized by recurrent bacterial infections,
especially ear, sinus, and lung infections.
Patients are also susceptible to periodontal infections.
Aggressive periodontitis is a common finding in children
who are diagnosed with agammaglobulinemia
56

57. Conclusion
A wide array of disorders of blood encountered in internal medicine has manifestations in the
oral cavity and the facial region.
Most of these manifestations are non-specific, but should alert the hematologist and the
dental surgeon to the possibilities of a concurrent disease or a latent one that may
subsequently manifest itself.
These manifestations must be properly recognized if the patient must receive appropriate
diagnosis and referral for treatment. Proper diagnosis is essential to initiate the correct
treatment
57

58. References
Davidson’s principles and practice of medicine
Essentials of medical physiology- Sembulingam
Adeyemo TA, Adeyemo WL, Adediran A, Akinbami AJ, Akanmu AS. Orofacial manifestations of
hematological disorders: Anemia and hemostatic disorders. Indian Journal of Dental Research.
2011 May 1;22(3):454.
Caranzza 12th edition
Deas DE, Mackey SA, McDonnell HT. Systemic disease and periodontitis: manifestations of
neutrophil dysfunction. Periodontology 2000. 2003 Jun;32(1):82-104.
58