platelet structure, disorder, thrombopoesis, dental considerations, Idiopathic Thrombocytopenic purpura, Thrombotic thrombocytopenic purpura, laboratory diagnosis of platelet disorders

1. PLATELET DISORDERS
Presented by: Neha Bemalgi
Department of Pedodontics
AME’s Dental College and Hsopital
First year pg

2. CONTENTS:
 What is a Platelet?
 Thrombopoiesis
 Structure & Function of platelets
 Basic mechanism of Hemostasis
 Coagulation pathways
 Clinical features & Lab investigations
 Platelet Disorders
 Dental considerations.
 Management
 Pediatric dental therapy
 Coagulation Disorders.
 References

3. PLATELETS OR
THROMBOCYTES
INTRODUCTION:
 These are biconvex discoid structures with 2-3mm in
greatest diameter.
 Normal platelet count is 1,50,000 - 4,50,000/cumm.
 Life span of 8-12 days.

4. THROMBOPOESIS
 Platelets form in the bone marrow.
Thrombopoetin secreted by liver
Stimulates growth &maturation of
megakaryoblast
Immature megakaryocytes
Platelets

5. STRUCTURE OF PLATELET
1) Peripheral zone- rich in glycoproteins required
for platelet adhesion, activation & aggregation.
Eg: GP1b/IX/ ;GPIIb/IIIa.
2) Sol-gel zone- rich in microtubules &
microfilaments, allowing the platelets to maintain
discoid shape.

6. Alpha granules: factor V,VIII, fibrinogen, chemotactic
3)Organelle zone agents, platelet derived growth factor.
4)Membranous zone- contains membranes derived from
megakaryocytic smooth ER organized into a dense tubular system
which is responsible for thromboxane A2 synthesis.
Dense bodies: ADP, calcium, serotonin, which are
platelet activating mediators.

7. PLATELET STRUCTURE
2
3
4

8. BASIC MECHANISM OF
HEMOSTASIS
I) Vascular phase.
II) Platelet phase.
III) Coagulation phase.
IV) Fibrinolytic phase.

9. I. VASCULAR PHASE
Tissue injury
Serotonin,
histamine, PG’s, etc.,
Immediate vasoconstriction

10. II. PLATELET PHASE
1) PRIMARY HEMOSTASIS:
This occurs in three steps:
1) Platelet Adhesion
2) Platelet Activation
3) Platelet Aggregation

11. Von will

12. PLATELET ADHESION
 Normal vascular endothelium provides an
antithrombotic surface.
 When vascular endothelium is injured, the
platelets adhere to the exposed surface
primarily through GP Ia-IIa and also by
adhesion of GP Ib-IX to VWF (A protein that
is present in plasma and extra cellular matrix
of the sub endothelial vessel wall)

13. PLATELET ACTIVATION AND
AGGREGATION
 Collagen exposure results in swelling and irregular
pseudopod formation & contractile proteins contract
forcefully and cause release of platelet granule contents
(ADP, Factor Va, and thromboxane A2, serotonin).
 Serotonin helps in vasoconstriction, thromboxane A2
helps in aggregation.
 Aggregation is mediated by fibrinogen which forms
bridge between adjacent platelets via glycoprotein
receptors on platelets, Gp IIb – IIIa.

14.  Involves production of THROMBIN & FIBRIN.
Intrinsic
pathway
Extrinsic
Pathway
Common
Pathway
It involves three separate
pathways
(That begins in
the blood itself.)
(Begins with
trauma to vessel
wall or tissues)

15. CLOTTING FACTORS
 Factor I - Fibrinogen
 Factor II - Prothrombin
 Factor III - Tissue thromboplastin
 Factor IV - Calcium
 Factor V - Labile factor or proaccelerin
 Factor VII - Stable factor
 Factor VIII - Antihemophilic Factor A
 Factor IX - Antihemophilic Factor B or Christmas factor or PTC
 Factor X - Stuart Prower Factor
 Factor XI - Antihemophilic Factor C or PTA
 Factor XII -Hageman factor
 Factor XIII -Fibrin stabilizing factor

16. STAGES OF CLOTTING
Clotting occurs in 3 steps:
1) Formation of prothrombin activator
2) Prothrombin to thrombin
3) Fibrinogen to fibrin

17. Intrinsic pathway
XII --------> XIIa
XI -----XIa
IX -----> IXa
Extrinsic pathway
VIIIa, TF <----- Tissue damage
VIII,Ca2+
X----------------------> Xa <-------------------------- X
V,ca2+
Prothrombin(II) -----------------> Thrombin(IIa)
Fibrinogen--------------> Fibrin
Common pathway
COAGULATION PATHWAYS

18. IV. FIBRINOLYTIC PHASE
PLASMINOGEN
PLASMIN
FIBRIN,
FIBRINOGEN
FIBRIN DEGRADATION
PRODUCTS
t-PA & urokinase

19. CLINICAL FEATURES
AND
LABORATORY FINDINGS

20.  Bleeding from superficial cuts &
scratches.
 Spontaneous gingival bleeding.
 Petechiae (<3mm)
 Purpura (5-9mm)
 Ecchymosis (>1cm)
 Epistaxis.
 Deep dissecting hematomas.
 Hemarthrosis.

21. LABORATORY DIAGNOSIS
 Help to
- Identify deficiency of required elements
- Dysfunction of the phases of coagulation
• Platelet count
• Bleeding
Time
• PFA
• PT/INR
• PTT
• Capillary
Fragility Test.
LAB TESTS

22. PLATELET COUNT
 Normal-150,000 to 450,000/mm3
 If < 50,000/cumm
 In such cases platelet transfusion may be
necessary.
Hemorrhagic Stroke
Surgical haemorrhage
Traumatic haemorrhage etc.,
may occur.

23. BLEEDING TIME
 Asses adequacy of platelet function
 Normal BT range 1-6min
 Prolonged in platelet disorders and
with intake of drugs like Aspirin

24. PLATELET FUNCTION
ANALYZER-100
 It is used to asses the primary hemostasis.
 Blood is collected in a sample tube. This
blood is aspirated and passed through an
aperture in a membrane that is coated with
platelet agonists(ADP, epinephrine, collagen)
 The time taken for the aperture to close is
considered to be normal,
In case of Col-Epi membrane it is <180secs
In case of Col-ADP membrane it is <120secs
Disadvantages:
 Not specific.
 Use restricted
to research
trials.

25. PT/INR
 Used to determine clotting tendency of
blood.
 Measure factors I, II, V, VII,X (Extrinsic
pathway)
 Normal range : 11-13secs.

26. Blood withdrawn in a test tube.
Treated with liquid sodium citrate, which binds to all Ca++
ions and prevents clotting of blood.
Blood is then centrifuged to separate blood cells and plasma.
Plasma is transferred to a measuring tube on which the blood
to citrate ratio would be specified by the manufacturer.

27. Next an excess of Ca++ is added to test tube, therefore
reversing the effect of citrate and enabling blood clot.
Finally, in order to activate the extrinsic pathway, TF
is added to the sample.
Time taken by the sample to clot is now measured.

28.  The results obtained for PT may vary considerably in an
individual if there are between different types of tissue
factor used in the reagent to perform the test.
 INR was devised to standardize the results, each
manufacturer assigns an ISI value (International Sensitivity
Index) for any tissue factor they manufacture.
 INR =( )
Why was INR introduced instead of PT?
PT test
PT normal
ISI

29. PARTIAL
THROMBOPLASTIN TIME
 Allows to asses body’s ability to form
clot through intrinsic pathway.
 Normal – 25 to 35seconds.
 May be prolonged incase of vWD, DIC,
hyperfibrinogenaemia, aspirin, warfarin,
liver diseases.

30. TORNIQUET TEST/ RUMPLE
LEEDE TEST
 Assesses fragility of capillary walls.
 This test is a part of WHO algorithm for
diagnosis of Dengue fever.
 A BP cuff is applied and inflated to the
midpoint of systolic and diastolic BP for
5mins.
 The test is positive if there are more than 10-
20 petechiae per square inch.

31. PLATELET DISORDERS
I) DISORDERS OF VESSEL WALL
II) QUALITATIVE DISORDERS
III) QUANTITATIVE DISORDERS
INHERITED
ACQUIRED
THROMBOCYTOPENIA
THROMBOCYTOSIS

32. I) VESSEL WALL DISORDERS
CAUSES
CONGENITAL
Heriditary
hemorrhagic
telangiectasia.
Vascular Ehler
Danlos Syndrome.
ACQUIRED
Henoch-Scholein purpura.
Vitamin C deficiency.
Hemolytic Uremic
Syndrome.
Simple easy bruisability.

33. HEREDITARY HEMORRHAGIC
TELANGECTASIA
 It is an uncommon autosomal dominant
disorder.
 Characterised by abnormally dilated
capillaries, these telangiectasias develop
particularly in skin, mucous membrane and
internal organs.

34. EHLER DANLOS
SYNDROME
 Rare autosomal dominant disorder caused by defect in type 3
collagen which results in fragile blood vessels, organ
membranes, leading to bleeding and organ ruptures.
 As of 2017, 13 types of EDS have been classified.
 The diagnosis should be considered when there is normal lab
test but patient has history of bleeding.

35. VITAMIN C DEFICIENCY
 Vit C is essential for collagen formation.
 Occurs when Vit C levels fall below 10mg/d.
 Haemorrhage in muscles, joints, nail beds and
gingival tissue.
 Gingiva – swelling, bleeding, secondary infection,
loosening of the teeth.
TREATMENT:
Diet rich in Vit C/ administration of 1gm/d vit c
supplements.

36. II) QUALITATIVE DISORDERS
A) CONGENITAL
 Glanzmann’s thrombasthenia
(absence of platelet GpIIbIIIa
receptor)
 Bernard Soulier Syndrome
(absence of theplatelet GPIb-IX
receptor)
 Storage pool disease (absence
of dense granules)
B) ACQUIRED
 Aspirin Therapy
 Uremia
 Chronic Renal
Failure.

37. INHERITED QUALITATIVE
PLATELET DISORDERS
BERNARD SOULIER SYNDROME
(Defective Adhesion)
 It is an autosomal recessive disorder, with
large platelets having defective binding to
VWF, defective adherence to exposed
subendothelial connective tissues, thus
platelets do not adhere.
Menorrhagia
Epistaxis
Bleeding
gums

38. GLANZMANN THROMBASTHENIA (Defective
Aggregation)
 Autosomal recessive disorder, failure of primary
platelet aggregation because of deficiency of
membrane GPIIb-IIIa.
STORAGE POOL DISEASE
 An autosomal dominant disorder, abnormalities in
platelet granule formation.

39. TREATMENT FOR
CONGENITAL
QUALITATIVE DISORDERS
 Platelet transfusion if severe bleeding occurs.
 Milder bleeding symptoms respond to desmopressin
(increases levels of vWF and factor VIII levels, it may
also have direct effect on platelet function.) can be
administered as IV (0.3mcgm/kg) or intranasally.
 Increased vwf levels for next 18-24hours.

40. ACQUIRED QUALITATIVE
PLATELET DISORDER
I) Cardiopulmonary bypass surgery
o Surgery itself is a major reason which leads to
mechanical destruction of platelets and the other
important cause is Heparin-induced
thrombocytopenia (HIT), which is seen in about
3% cases.
II) Cirhosis of liver
o Throbocytopenias due to insufficient throbopoetin.
III) Uremia
o Metabolites that are toxic to the paltelets
accumulate in the plasma.

41. QUANTITATIVE
ABNORMALITIES
 Thrombocytopenias
- Thrombocytopenia of Fanconi’s anemia.
- Thrombocytopenic Purpura.
• Idiopathic Thrombocytic Purpura
• Thrombotic Thrombocytopenic
Purpura
• Acquired Thrombocytopenic Purpura
 Thrombocytosis

42. THROMBOCYTOPENIA
1)Immunologic
thrombocytopenia:
ITP, Post transfusion,
Neo-natal.
2) Increased
consumption:
DIC,TTP, Viral
infectons, Hemolytic
anemias
1)BM FAILURE:
Aplastic anemia,
leukaemia,carcinoma
2) Drugs:
Quinine,quinidine,rif
ampicin,sulfonamide
s
Decreased
production
Increased
destruction
Splenic
sequestration
Dilution
loss
No platelets are stored in
the bone marrow. If a
condition causes
the spleen to enlarge
(splenomegaly),
the spleen will function
abnormally, sequestering
up to 90% of the total
platelet mass in
the spleen

43. IDIOPATHIC
THROMBOCYTOPENIC
PURPURA (ITP)
 It is an autoimmune disorder of platelets
 Platelet count may reduce to as low as
20,000/ml.
Causes
Autoantibodies are formed against the
membrane GPIIb-IIIa, leading to destruction
and removal of platelets from circulation by
splenic macrophages.
TYPES
ACUTE ITP CHRONIC ITP

44. ACUTE ITP
 Seen in children recovering
from viral illness, after 2-
3weeks.
 Sudden onset of purpura, oral
& nasal bleeding.
 90% Recovery occurs within
3-6moths.
 MOA:Antibodies produced
against viral Antigen cross
react with platelets.
CHRONIC ITP
 Mostly in females of
child bearing age
group(20-40yrs)
 May occur in association
with other autoimmune
disorders, like SLE,
thyroid disease,
lymphocytic leukaemia.
 Antibodies are directed
against membrane GP
IIb-IIIa.

45. DIAGNOSIS:
 Platelet count < 60,000/cumm.
 Bleeding time is often increased to an hour.
 Abnormally large
platelets(megathrombocyte)
 Prolonged BT.

46. TREATMENT :
 Corticosteroids- Prednisolone:1-2mg/kg/day
-Dexamethasone40gm/day for 4 days
then repeat after 4weeks, because it is an
immunosppresant it reduces production of Ab’s.
 Anti-D Ig - following administration, anti-D-coated red
blood cell complexes saturate Fcγ receptor sites
on macrophages, resulting in preferential destruction of red
blood cells (RBCs), therefore sparing antibody-
coated platelets. There are two anti-D products indicated for
use in patients with ITP: WinRho SDF and Rhophylac
 Spleenectomy
 Bone Marrow Transplantation

47. THROMBOTIC
THROMBOCYTOPENIC
PURPURA
 Uncommon form of thrombocytopenia.
 In 1925 Moschcowitz observed widespread hyaline
thrombi in capillaries and arterioles now established
as the pathologic hallmark of TTP.

48.  TTP arise from autoantibody-mediated inhibition of
the enzyme ADAMTS13, a metalloprotease responsible for
cleaving large multimers of von Willebrand factor (vWF) into
smaller units. The increase in circulating of large multimers
of vWF increases platelet adhesion to areas
of endothelial injury, particularly
where arterioles and capillaries meet, which in turn results in
the formation of small platelet clots called thrombi.

49. CLINICAL FEATURES:
 Seen in young adults
 Females> males
 Thromcocytopenia
 Hemolytic anemia
 Fever
 Transitory neurologic dysfunction
 Renal failure

50. LAB DIAGNOSIS:
◊ Hemoglobin-usually less than 10.5 g/dl
◊ Thrombocytopenia is typically severe (8 to 44/μl)
due to consumption of platelets in the formation of
microthrombi.
◊ Megakaryocytes are abundant in the bone marrow.
◊ The bleeding time may be prolonged.
◊ CT – normal usually

51. TREATMENT:
◊ Plasma exchange recently became the standard therapeutic
management for this disease. Plasma exchange regiments for TTP
should begin with single plasma volume exchange (40 ml/kg body
mass) on a daily basis. Daily treatments should continue until the
resolution of the thrombocytopenia, neurological abnormalities,
the stabilization of the hemoglobin
◊ Spleenectomy.

52. THROMBOCYTOSIS
◊ Increase in no. of circulating platelets
 TYPES
◊ Primary - incase of bone marrow disorder
(myeloproliferative disorders)
◊ Secondary- may occur after traumatic injury, surgical
procedure or parturition. Also been associated with
polycytehmia, TB, sarcoidosis, rheumatoid arthritis.

53. CLINICAL FEATURES:
◊ Even though platelet count is elevated bleeding tendency
is seen
◊ Epistaxis, prolonged bleeding after extraction, gingival
bleeding.
◊ Bleeding in GIT, genitourinary tract & CNS is common
◊ Hemorrhage into the skin

54. LAB DIAGNOSIS:
◊ Platelet count is increased
◊ Abnormal platelet aggregation
◊ CT, PT, clot retraction & tourniquet test is normal
◊ BT is increased.

55. TREATMENT :
 Selective administration of low dose aspirin( 65mg) to
minimize the risk of stroke or thrombosis.

56. DENTAL
CONSIDERATIONS

57.  Major surgery requires platelet count above 75X109 /L.
 If platelet count is low then platelet transfusion may be
done.
 The thrombasthenic patient needing dental extractions may
be successfully treated with the use of hemostatic measures
such as microfibrillar collagen and antifibrinolytic drugs or
topical application of platelet concentrate.

58. † Avoid aspirin 1-2 weeks prior to extensive surgical
procedure as aspirin action remains for 8- 10 days
† Other NSAIDs have a similar but less pronounced
antiplatelet effect. Local hemostatic agents are useful in
preventing postoperative oozing when aspirin therapy is in
use at the time of minor oral surgery.
† When extensive surgery is emergently indicated, DDAVP
can be used to decrease the aspirin-induced prolonged BT.

59. PEDIATRIC
CONSIDERATIONS
Administration of factor concentrates and extraction of
deciduous tooth with curettage may be necessary for patient
comfort and hemorrhage control.
Moss advocates extraction of mobile primary teeth using
periodontal space anesthesia without factor replacement after
2days of vigorous oral hygiene to reduce local inflammation.

60. Stainless steel crowns should be prepared to allow
minimal removal of enamel at gingival areas.
Preventive measures: topical flourides ,use of pit &
fissure sealants.

61. COAGULATION
DISORDERS

62. HEPARIN
COUMARIN
LIVER DISEASE
VIT K DEFICIENCY
FIBRINOLYTIC DISEASES
DIC

63. HAEMOPHILIA A & B
 Both types of haemophilia
share same symptoms &
inheritance pattern, only blood
tests can differentiate.
 Important to know which factor
is defective to give correct
treatment

65. HEMOPHILIA A
 Hereditary bleeding disorder - deficiency in factor VIII in
plasma.
 X chromosome-linked hereditary transmission.
Diagnosis:
 Usually established from clinical history.
 Suspected from a family history of bleeding only in males,
exaggerated bleeding response to minor traumas /dental
manipulation.

66. NORMAL RANGE 50 – 150% Clotting
Factor
Normal blood coagulation
MILD HAEMOPHILIA 5-50% Clotting Factor Bleeding problems usually
associated with extractions,
surgery, often not diagnosed
until later part of life.
MODERATE
HAEMOPHILIA
2-5% Clotting Factor Bleeding associated with
knock/deep cut.
Can present severe hemophilia
SEVERE HAEMOPHILIA <1% Clotting Factor Bleeding frequently in joints,
smooth muscles & brain.
Usually diagnosed in 1st year of
life

67.  Definitive diagnosis - by quantization of
procoagulant activity of FVIII (reduced)
-DNA analysis - to detect carriers & to establish a
prenatal diagnosis.
-Preimplantation genetic diagnosis- parents at risk of
transmitting disease can know whether embryo is
affected or not
 Differential diagnosis - established with Von
Willebrand’s disease.

68. CHRISTMAS DISEASE
 Christmas disease - congenital coagulation disorder,
quantitative/qualitative anomaly of factor IX.
 Five times less common than hemophilia A & clinically
indistinguishable.
 Diagnosis.
-PT & BT are normal.
-Definitive diagnosis by quantitation of
procoagulant activity of FIX (reduced)

69. ORAL MANIFESTATIONS
 Experience many episodes of oral bleeding
 Location of oral bleeds:
Labial frenum-60%, Tongue-23%
Buccal mucosa- 17%, Gingiva & palate 0.5%
 Rarely hemarthrosis of TMJ
 Severe periodontal disease.

70. LABORATORY DIAGNOSIS

71. PRE SURGERY TREATMENT
FOR HEMOPHILIA

72. DDAVP (1-deamino-8-D arginine
vasopressin)
 Synthetic vasopressin analog , stimulates FVIII
& vWF release from endothelial cells & also
increases platelet adhesion.
 Provides adequate transient coagulation factors
in mild to moderate haemophilia.
 Advantage - avoidance of use of plasma
concentrates, low cost & absence of viral risk
 Results in mean of a 2-5 fold rise in F VIII
activity & vWF antigen

73. ANTIFIBRINOLYTIC
TREATMENT
 The two most widely used drugs
A) ε-aminocaproic acid (EACA, Caproamin)
B) tranexamic acid (AMCHA, Amchafibrin).
 Bind to plasminogen binding site - inhibition of fibrinolysis .
 Oral, iv / topical routes with following doses:
-EACA 300 mg/kg/day every 4-6 hrs;
-AMCHA 30 mg/kg/day in 2-3 daily doses

74. TRANEXAMIC ACID
 Prevents plasmin binding to fibrin
 prevents fibrin breakdown
 Supplied as 10% solution
 Dilute with 5ml water - 5% solution
 on gauze swab - bite pack
 oral rinse - 4 x daily for 1 week (rinse & spit)

75. TOPICAL HEMOSTATIC
AGENTS

76. GENE THERAPY
 The therapy uses a viral vector to transfer a
functional copy of the gene responsible for
producing FVIII, which is mutated in
people with hemophilia A, into the patient’s
body.
 In contrast to standard care, which requires
multiple intravenous therapy infusions per
week, this gene therapy appears to have
long-lasting effects after a single infusion.
First Successful Gene Therapy Trial Reported for People with
Hemophilia A
Report published in new England journal of medicine by Rangarajan et
al in Dec 2017

77.  Prior to this study, participants received up to 185 FVIII
infusions per year to prevent bleeds, resulting in up to 41
breakthrough bleeding episodes per year despite
prophylactic treatment. After receiving the gene therapy, all
patients were able to completely discontinue prophylactic
FVIII infusions, and 10 had no bleeding episodes requiring
FVIII treatment from four weeks after infusion through the
last follow-up visit.

78. DENTAL CONSIDERATIONS
 Periodontal Treatment
- Probing & supragingival scaling  no factor replacement
- Deep scaling, curettage & surgery  factor replacement
 Orthodontic Treatment
- Fixed preferred over removable
- Extra oral force & short treatment duration
- Minor intraoral bleeding  pressure application

79. Pediatric Treatment
 Loose primary teeth oral hygiene program for two days
 extraction under periodontal anaesthesia
 Pulpotomies -without excessive bleeding
 Stainless steel crowns- minimal removal of enamel at
gingival areas
 Use of topical fluorides and pit & fissure sealants

80. Restorative & Prosthodontic Treatment:
 Without factor replacement
 Rubber dam to protect oral tissues
 Wedges- protect & retract papilla
 Pulpal bleeding- controlled by conventional methods
 Avoid over instrumentation & filling
 Denture trauma minimized by prompt & careful post insertion
adjustment.

81. VON WILLEBRAND
DISEASE
 Pseudohemophilia / Vascular hemophilia
 Autosomal dominant, F>M
 Results from quantitative / qualitative defects in vWF. vWF
is carrier of F VIII in plasma; deficiency - low levels of F
VIII
 Mucosal bleeding, epistaxis ,easy bruising, menorrhagia in
women & rare hemarthrosis

82.  Type 1: Most common, shows lower than normal levels of VWF in the
body. Mild bleeding symptoms.
 Type 2: Normal level of VWF but has structural and functional defects
 Type 3: Most dangerous type, VWF is not produced. As a result of
which platelets wont be able to clot. Hemarthrosis, epistaxis,
menorrhagia are seen. Usually detected during childhood.

83. DIAGNOSIS
a) Quantitative measures of vWF
b) Functional assays of vWF
c) Multimer analysis.
 Assays help to make diagnosis & define subtype.
Discrimination among subtypes important - clinical &
therapeutic implications.

84. MANAGEMENT
 Type I- DDAVP
 Type II & III – intermediate purity factor VIII
concentrates, platelet concentrate infusion.

86. OTHER INHERITED
COAGULATION DISORDERS
Factor XI Deficiency :
- Uncommon autosomal recessive disorder
- Bleeding mild, manifest only after surgical or dental
procedures
- Treatment  fresh frozen plasma

87. Factors V, VII, X & Prothrombin deficiencies
- Associated with mild to moderate bleeding disorders
- Treatment  fresh frozen plasma, prothrombin complex
concentrate
Factor XIII Deficiency :
- Effects cross-linking of fibrinogen & stabilization
- Treatment  fresh frozen plasma or cryoprecipitate

88. CONCLUSION
 Dental procedures resulting in bleeding can have serious
consequences in a patient having bleeding
disorder……… severe hemorrhage or even death.
 So one should have thorough sound knowledge in order
to save a life and to have a good practice

89. REFERENCES
 Guyton and Hall, Text book of Physiology, 12th edition.
 Burkets Oral Medicine & Diagnosis& Treatment, 9th
edition.
 Robbin’s pathologic basis of disease, 7th edition
 Harsh Mohan, Textbook of Pathology, 5th edition.
 Davidson’s Principles & Practice of medicine, 17th
edition.