This document discusses blood coagulation and the coagulation cascade. It describes the three stages of hemostasis: vascular phase, platelet phase, and coagulation phase. The coagulation phase involves both intrinsic and extrinsic pathways leading to a blood clot through the conversion of fibrinogen to fibrin. Key factors in the coagulation process require calcium, vitamin K, phospholipids and thrombin to activate clotting factors and form a stable blood clot. Testing and management of bleeding disorders is also addressed.

1. BLOOD COAGULATION
CASCADE
Dr. K. Nikhitha
1st MDS
Department of Periodontology

2. CONTENTS:
 INTRODUCTION
 HEMOSTASIS
 STAGES OF HEMOSTASIS
 VASCULAR PHASE
 VON WILLEBRAND FACTOR
 PLATELET PHASE
 COAGULATION PHASE
 FACTORS INVOLVED IN BLOOD CLOTTING
 SEQUENCE OF CLOTTING MECHANISM
 CURRENT CONCEPT OF COAGULATION
 BLOOD CLOT
 „CLOT RETRACTION
 FIBRINOLYTIC PHASE 2

3.  ROLE OF THROMBIN
 ROLE OF CALCIUM
 ROLE OF VITAMIN-K
 ROLE OF PHOSPHOLIPIDS
 CLASSIFICATION OF DISORDERS OF COAGULATION
 TESTS FOR BLOOD CLOTTING
 SIGNIFICANCE OF BLEEDING DIORDER IN THE TREATMENT OF
PERIODONTAL DISEASE
 MANAGEMENT OF PERIODONTAL PATIENTS WITH BLEEDING DISOREDERS
 CONCLUSION
 REFERENCES
3

4. INTRODUCTION:
 Delivery of patient care encompasses a wide variety of challenges, one of
which is unexpected clinical bleeding.
 Clinical bleeding can be presented in two forms:
the first can occur during surgery; and
the second can manifest several days after the procedure.
 In both situations, the clinician must take immediate action to control the
hemorrhage and stabilize the patient.
4

5.  As the medically compromised patients increases with the aging
population, manifest signs of periodontal disease.
 Polypharmacia and medical conditions, may contribute to the tendency for
excessive bleeding.
 Treatment of periodontal disease, either by surgical or non-surgical
procedures more or less involves increased risk of bleeding in those
patients.
 However, spontaneous bleeding can occur in sites of significant tissue
inflammation (gingivitis & periodontitis) because of increased vascularity.
5

6.  Although the incidence of bleeding disorders is low in the general
population, a hemorrhagic episode during or after periodontal procedures
can lead to detrimental complications.
 Therefore, it is necessary for the periodontist to have a good working
knowledge of the hemostatic mechanism and be prepared to manage
locally and reconsider treatment approaches in patients with bleeding
disorders and periodontal disease.
6

7. HEMOSTASIS :
Hemostasis is defined as arrest or stoppage of bleeding.
The word “Haemostasis” comes from Greek,
‘haeme’ means blood
‘stasis’ means to stop.
STAGES OF HEMOSTASIS:
1. Vasoconstriction
2. Platelet plug formation
3. Coagulation of blood. 7

8. *Vassilopoulos P, Palcanis K. Bleeding disorders and periodontology. Periodontol 2000. 2007;44:211-23.
8
Vascular
phase
•Smooth cells
contraction
Platelet
phase
•Adhesion
•Activation
•Secretion
•Aggregation
Coagulation
phase
•Tissue
factor –
dependent
•Intrinsic
Fibrinolytic
phase
•Lysis of
fibrin
network
into
peptides
•Fibrinogen
deactivation
HEMOSTASIS

9. 9

10. VASCULAR PHASE:
 Immediately after injury, the blood vessel constricts and decreases the
loss of blood from damaged portion.
 Usually, arterioles and small arteries
constrict.
 Vasoconstriction is purely a local
phenomenon.
10

11. Injury to the blood vessel , endothelium gets damaged
Exposure of Collagen
von willebrand factor
Adherence of platelets to the collagen
Activation of platelets
Secretion of serotonin
Vasoconstriction
11

12. von Willebrand factor:
12
 It is composed of a series of plasma protein multimers.
 Originally presented in the form of a propeptide in the endothelial and
megakaryocyte cells.
 It acts as a connecting link between the injured subendothelial collagen
and a specific glycoprotein present on the surface of platelet, providing an
aggregate of platelets at the bleeding site.

13. PLATELET PHASE:
PLATELETS :
Discovered by Giulio Bizzozera in 1882.
 Platelets are disc shaped , anucleate
cellular fragments.
 Derived from megakaryocytes in the bone marrow
& circulate in the periphery of the vascular lumen.
 2-4µm in diameter.
 Normal platelet count : 1,50,000–4,00,000/µl.
13

14. Platelet membrane
14
Outer layer
Glycocalyx layer
(Glycoprotein)
Adhesion
Inner layer
Lipoprotein layer
Various lipid molecules
Phospholipids
Activates intrinsic
pathway
Normal hemostasis
+ Protein enzyme-
Adenyl cyclase
Enhances platelet
function

15. Platelet Granule Content:
Alpha granules Dense granules
Fibrinogen Serotonin
PDGF Calcium
TGF β ATP
P selectin ADP
Albumin Pyrophosphate
vWF
Fibronectin
Factor V
α 2 macroglobulin
Vitronectin
α 1 -proteinase inhibitor
15

16.  The platelet phase is characterized by
Platelet adhesion,
Platelet activation,
Platelet secretion and
Platelet aggregation.
 The platelets adhere to the exposed subendothelial connective tissue
through glycoprotein receptors located in the platelet membrane.
(Platelet adhesion)
 Glycoprotein receptors GP Ib-IX-V and GP Ia-IIa, as well as GP VI, play a
predominant role in the binding of platelets at the site of injury.
16

17.  Von Willebrand factor acts as a bridge
between GP Ib-IX-V and underlying
collagen and, as a result, initiates
platelet activation.
 With this bridging, the platelet is
able to move towards the direction of
blood flow until it binds firmly to the
vascular wall through the GP Ia-IIa
and GP VI receptors.
17

18.  The activation of platelets leads to the formation of filopodia and, at this
time, the platelet cell is prepared for secretion.
 The first wave of platelet aggregation ends before platelet granule
secretion. The second wave begins with the granule release (Secretion).
 Platelets contain a number of storage granules, as well as glycogen
particles, mitochondria and lysosomes.
18

19.  Both categories of granules play an important role in hemostasis.
 The second wave of platelet aggregation is associated with hemostatic plug
organization through the binding of GP IIb–IIIa receptor with fibrinogen.
19

20. ADP = Adenosine diphosphate; PAF = Platelet-activating factor
Stages of Hemostasis * Essentials of physiology-
SEMBULINGAM 6th ed
20

21. MECHANISM OF PLATELET
AGGREGATION AND INHIBITION
21

22. COAGULATION PHASE:
Coagulation or clotting is defined as the process in which blood loses
its fluidity and becomes a jelly-like mass few minutes after it is shed out or
collected in a container.
CLASSIFICATION OF COAGULATION
FACTORS:
22

23. 23
FACTORS INVOLVED IN BLOOD
CLOTTING :

24. 24
CLOTTING FACTORS AND THEIR
FUNCTIONS:

25. Stages of Blood Clotting
In general, blood clotting occurs in three stages:
1. Formation of prothrombin activator
2. Conversion of prothrombin into thrombin
3. Conversion of fibrinogen into fibrin.
STAGE 1: FORMATION OF PROTHROMBIN ACTIVATOR
 Formation of prothrombin activator occurs through two pathways:
i. Intrinsic pathway
ii. Extrinsic pathway.
25

26. Intrinsic Pathway :
 In this pathway, the formation of prothrombin activator is initiated by
platelets.
Extrinsic Pathway :
 In this pathway, the formation of prothrombin activator is initiated by the
tissue thromboplastin, which is released from the injured tissues.
26

27. 27
Stages of blood coagulation
a = Activated,
HMW = High molecular
weight.

28. STAGE 2: CONVERSION OF PROTHROMBIN INTO THROMBIN
Prothrombin and Thrombin:
 Prothrombin is a plasma protein, an α 2-globulin.
 Molecular weight- 68,700.
 Normal plasma concentration -15 mg/dl.
 It is an unstable protein that can split easily into smaller compounds, one
of which is thrombin (molecular weight - 33,700)
28

29.  Vitamin K is required by the liver for normal activation of prothrombin, as
well as a few other clotting factors.
 Therefore, either lack of vitamin K or the presence of liver disease
prevents normal prothrombin formation which results in decreased
prothrombin level leading to increased risk of bleeding.
29

30. 30
Stages of blood coagulation
a = Activated,
+ = Thrombin induces
formation of more thrombin
(positive feedback);
HMW = High molecular
weight.

31. STAGE 3: CONVERSION OF FIBRINOGEN INTO FIBRIN
Fibrinogen:
 Fibrinogen is a high-molecular-weight protein (MW = 340,000)
 Plasma concentration of fibrinogen -100 to 700 mg/dl.
 Liver disease can decrease the concentration of circulating fibrinogen.
31

32. 32
Stages of blood coagulation
a = Activated,
+ = Thrombin induces
formation of more thrombin
(positive feedback);
HMW = High molecular
weight.

33. CURRENT CONCEPT OF COAGULATION:
 Current evidence supports the understanding that intrinsic pathway is not
a parallel pathway but indeed it augments thrombin generation primarily
initiated by the extrinsic pathway
 Newer model describes coagulation with four steps:
1. Intiation
2. Amplification
3. Propagation
4. Stabilization 33

34. INITIATION:
 It occurs by expression of Tissue factor (TF)
in damaged vessel which binds factor VIIa
to activate factor IX and factor X.
 This activation of factor IX by TF-VIIa
complex serves as the bridge between
classical extrinsic and intrinsic pathways.
 Factor Xa then binds to factor II to form
thrombin (factor IIa). Thrombin generation
through this reaction is not robust and can
be effectively terminated by TF pathway
inhibitor.
34

35. AMPLIFICATION :
 Since the amount of thrombin generated is not sufficient, numerous
positive feedback loops are present that bind thrombin with platelets.
 Thrombin that is generated in the initiation phase further activates factor
V and factor VIII, which serves as a cofactor in prothrombinase complex.
 This accelerates the activation of Factor II by F Xa and F Xa by F IXa,
respectively.
35

36. 36
PROPAGATION:
• The accumulated enzyme complexes
on platelet surface support robust
amounts of thrombin generation
and platelet activation.
• This ensures continuous generation
of thrombin and subsequently fibrin
to form a large clot.

37. STABILIZATION:
 Thrombin generation leads to activation of factor XIII (fibrin stabilizing
factor) which covalently links fibrin polymers and provides strength and
stability to fibrin incorporated in platelet plug.
 In addition, thrombin activates thrombin activatable fibrinolysis inhibitor
(TAFI) that protects the clot from fibrinolysis.
37

38. 38
 It is composed of a meshwork of fibrin fibers entrapping blood cells,
platelets, and plasma.
 Fibrin fibers adheres to the opening of damaged blood vessel and prevents
further blood loss.
 The trapped RBCs are responsible for the red color of the clot.
 The external blood clot is also called scab.
BLOOD CLOT:

39. 39
 Within a few minutes after a clot is formed, it begins to contract.
 Straw-colored serum oozes out of the clot within 20 to 60 minutes.
 Contractile proteins namely actin, myosin and thrombosthenin in the cytoplasm
of platelets are responsible for clot retraction.
 The contraction is activated and accelerated by thrombin, as well as by calcium
ions released from calcium stores in the cell organelles of the platelets.
 As the clot retracts, the edges of the broken blood vessel are pulled together, thus
contributing further hemostasis.
CLOT RETRACTION :

40. 40
 Lysis of blood clot inside the blood vessel is called fibrinolysis.
 It is the last stage of hemostasis and initiates disintegration of the
hemostatic plug and the tissue repair process.
 This process requires a substance called plasmin or fibrinolysin.
Formation of Plasmin:
 Plasmin is formed from inactivated glycoprotein called plasminogen.
 Plasminogen is synthesized in liver and it is incorporated with other
proteins in the blood clot.
FIBRINOLYTIC
PHASE:

41. 41
Sequence of Events Involved in the Activation of Plasminogen:
1. During intravascular clotting, the endothelium of the blood vessel
secretes a thrombin-binding protein, the thrombomodulin. It is secreted by
the endothelium of all the blood vessels, except the minute vessels of brain.
2. Thrombomodulin combines with thrombin and forms a thrombomodulin-
thrombin complex.
3. Thrombomodulin-thrombin complex activates protein C

42. 42
4. Activated protein C inactivates factor V and VIII in the presence of a
cofactor called protein S
5. Protein C also inactivates the t-PA inhibitor
6. Now, the t-PA becomes active
7. Activated t-PA and lysosomal enzymes activate plasminogen to form
plasmin. Plasminogen is also activated by thrombin and u-PA

43. 43

Fibrinolysis
t-PA = Tissue
plasminogen
activator
u-PA = Urokinase
plasminogen
activator

44. 44

45. 45

46. ROLE OF THROMBIN:
46

47. ROLE OF VITAMIN-K:
47
 Vitamin-k brings out the post translational modification of blood clotting
factors .
 Factor II , VII , IX , & X are synthesised as inactive precursors in the
liver.
 Vitamin-k coenzyme – carboxylation of glutamic acid residues present in
the proteins and this reaction is catalysed by a carboxylase.

48. 48
Deficiency
of vitamin-k Lack of active prothrombin in the circulation
results in
Adversely affected blood coagulation
Individual profusely bleeds even for minor injury
Blood clotting time is increased

49. ROLE OF CALCIUM:
49
 Except for the first two steps in the intrinsic pathway, calcium ions are
required for promotion or acceleration of all the blood-clotting reactions.
 Therefore, in the absence of calcium ions, blood clotting by either pathway
does not occur.

50. 50
subendothelium platelet
binds ca++ influx
vWF
Stimulates
Release of ca dependent enzymes
Regulates the platelet metabolism & secretion of many active
substances
Increased intracellular
calcium conc

51. 51
 In the body, the calcium ion concentration seldom falls low enough to
significantly affect the kinetics of blood clotting.
 When blood is removed from a person
prevented from clotting
calcium ion concentration
(deionizing the calcium by causing it to react with substances such as
citrate ion or by precipitating the calcium with substances such as oxalate
ion.)

52. ROLE OF PHOSPHOLIPIDS:
52
Activated platelets
provide
catalytic phospholipid surface ["tenase" (FIXa-F VIIIa)
&"prothrombinase" complex (F Xa-F Va) ]
Formation of a procoagulant platelet surface
involves
exposure of anionic phospholipids (e.g phosphatidylserine)
leads to
shedding of granules from the membranes of activated
platelets

53. 53
 Moreover, Tissue-factor, which plays a key role in blood coagulation by
initiating the extrinsic pathway, requires the presence of phospholipids
for optimal biological activity.
 The phospholipid dependency of the coagulation system explains the
prolongation of phospholipid dependent clotting tests in patients with
phospholipid directed antibodies such as lupus anticoagulants.

54. 54

55. TESTS FOR BLOOD CLOTTING:
55
 Blood clotting tests are used to diagnose bleeding disorders.
1.Bleeding time(BT)
2. Clotting time(CT)
3. Prothrombin time(PT)
4. Partial prothrombin time(PPT)
5. International normalized ratio(INR)
6. Thrombin time(TT)

56. 56
BLEEDING TIME:
 It is the time interval from oozing of blood after a cut or injury till arrest of
bleeding.
 Normal duration - 3 to 6 minutes.
 Lack of any one of several clotting factors can prolong the bleeding time.
 Mainly lack of platelets : BT

57. 57
CLOTTING TIME:
 It is the time interval from oozing of blood after a cut or injury till the
formation of clot.
 Its normal duration - 3 to 8 minutes.
 Lack of clotting factors: CT
PROTHROMBIN TIME:
 It is the time taken by blood to clot after adding tissue thromboplastin to
it.
 It indicates the total quantity of prothrombin present in the blood.
 Normal duration -10 to 12 seconds.

58. 58
 Deficiency of prothrombin &
other factors like factors I, V, VII and X PT
PARTIAL PROTHROMBIN TIME :
 It is the time taken for the blood to clot after adding an activator such as
phospholipid, along with calcium to it.
 Also called activated partial prothrombin time (APTT).
 This test is useful in monitoring the patients taking anticoagulant drugs.

59. 59
 Normal duration - 30 to 45 seconds.
 Heparin or warfarin therapy and
Deficiency or inhibition of PPT
factors II, V, VIII, IX, X, XI and XII.
INTERNATIONAL NORMALIZED RATIO:
 It is devised to standardize measurements of prothrombin time.
 Normal range(healthy person) - 0.9 to1.3
 A high INR level (e.g., 4 or 5) indicates a high risk of bleeding
 A low INR (e.g., 0.5) suggests that there is a chance of having a clot.
 Patients on warfarin therapy usually have an INR of 2.0 to 3.0

60. 60
THROMBIN TIME:
 It is the time taken for the blood to clot after adding thrombin to it.
 It is done to investigate the presence of heparin in plasma or to detect
 fibrinogen abnormalities.
 Normal duration -12 to 20 seconds.
 In heparin therapy &
dysfibrinogenimia TT

61. 61
CLOT SOLUBILITY TEST:
 This test detects the deficiency of factor XIII .
 This test is based on solubility of non crosslinked fibrin.
 Low F XIII is seen in inherited F XIII deficiency, F XIII inhibitors
(isoniazide, pencillin, sodium valproate)

62. SIGNIFICANCE OF BLEEDING DIORDER
IN THE TREATMENT OF PERIODONTAL
DISEASE:
 The extent and severity of periodontal disease determines the necessity for
a surgical or nonsurgical treatment approach in its management.
 Both of the above share the common goal of debriding the root surfaces.
 Periodontal cases can be more complicated and treatment may involve
tooth extractions and dental implant surgical procedures in order to
restore loss of function.(increased risk of bleeding)
62

63. 63
 The dental professional must be aware of the possibility that periodontal
patients with no previous indication of bleeding can manifest their first
bleeding event in the dental office.
 So, a detailed knowledge of intra-operative and postoperative hemostatic
measures under challenging hemorrhagic situations is considered a priority
for the dental care professional.

64. MANAGEMENT OF PERIODONTAL
PATIENTS WITH BLEEDING
DISOREDERS:
64
Management
Pre-operative
precautions
Intra-operative
actions
Post-operative
measures

65. 65
PRE-OPERATIVE PRECAUTIONS:
 Management starts with a medical history focusing on the previous
bleeding history of the patient and medical conditions associated with
bleeding.
 Medical history must include :
Previous hemorrhagic episodes after trauma or surgery, or even
spontaneous bleeding.
Family history regarding hereditary bleeding disorders.

66. 66
Current illnesses such as hepatic and renal failure
List of medications interfering with hemostasis, such as
NSAIDS
Antibiotics
Anticoagulation medications

67. 67
PATIENTS WITH HEREDITARY BLEEDING DISORDER:
 Consultation with physician and a hematologist is deemed necessary.
 The nature and severity of bleeding disorder and degree of invasive dental
procedures, determine the need for treatment to be provided in a
specialized treatment center setting.
 So, if necessary hematologist will advice the proper pharmocological
regimen to be administered prophylactically in order to achieve
hemostasis.

68. 68
PATIENTS WITH CERTAIN ILLNESSES:
 Prone to bleeding during deliver of dental treatment.
 The treatment protocol may have to be modified to minimize the risk of
intra-operative and postoperative bleeding.

69. 69
RENAL FAILURE:
 Managed day after dialysis when heparin has been cleaned from the
system and patient regains his/ her strength after dialysis process.
VITAMIN – K def:
 Should require vitamin –k supplement before the dental appointment to
restore liver function and the synthesis of coagulation factors.
LIVER FAILURE:
 Platelet transfusion in a hospital setting.

70. 70
ANTICOAGULANT THERAPY :
 Reduce risk of embolism and increase the probability of bleeding during
and after the dental procedure.
 So , detailed risk assessment has to be performed on each patient and the
possibility of life threatening situations has to be taken into serious
considerations before suggesting discontinuation of anticoagulants.

71. 71
COUMARIN:
 Decision of continuation , reduction or withstand of the medication based
on international normalised ratio value .
 </= 3.5 –periodontal surgical procedures can be carried in a dental office.
 > 3.5 – anticoagualant regimen has to be adjusted.
ASPIRIN:
 Dicontinue medication atleast 3 days and upto 7 days before the surgical
procedures.
 Consultation with the physician is mandatory.

72. 72
ANTIPLATELET DRUGS MEDIATORS:
(ADP inhibitors, Gp –II b III a inhibitors)
 Dicontinuation of the medication 7 days before the procedure gives
adequate time for the level of circulatory functional platelets to be
restored.

73. 73
INTRA-OPERATIVE MEASURES:
 Administered prior to or during the procedure to prevent unlikely
bleeding.
 Includes
1. Systemic measures
2. Local measures

74. 74
Various local hemostatic measures :
 Absorbable gelatin
 Absorable collagen
 Microfibrillar collagen & collagen dressings
 Oxidised regenerated cellulose
 Thrombin
 Tranexamic acid
 Epsilon – aminocaproic acid
 Fibrin glue
 Platelet rich plasma

75. 75
PLATELET TRANSFUSION
Systemically with replacement
of
coagulation factors
1 hr before the procedure
Inherited platelet disorder:
1. Moderate thromocytopenia
2. Severe thrombocytopenia
Inherited coagulopathies

76. 76
Acquired disorders
 Local measures like hemostatic
agents, antifibrinolytic mouthwashes
(tranexamic acid / epsilon
aminocaproic acid)
 Regional block anesthesia should be
avoided

77. 77
SURGICAL CARE :
 Meticulous handling of the soft tissues.
 Creating a conservative flap design .
 Minimising flap elevation.
 Application of moistened guaze on the flap for 10 min has been suggested.

78. 78
AFTER SURGERY :
Patients who are susceptible to bleeding
1. Instructed to bite on a moistened gauze /gauze soaked with hemostatic
agent for 30 minutes.
2. Check for bleeding after 30 min, if bleeding occurs ,additional measures
initiated.

79. 79
3. Surgical area rentered – bleeding spot identified
Soft tissues – laser & electrocautery
Hard tissues – Bone burnishing & bone wax
4. Once the bleeding is under control ,patient may leave the site with biting
guaze soaked with saline / tranexamic acid.

80. 80
POST-OPERATIVE MEASURES:
1. Good care of the surgical area.
2. Rinsing is prohibited on the day of the surgery.
3. Healing site must be left undisturbed.
4. Specific attention to the tongue movement.
5. Liquids & protien diet.
6. Use of antifibrinolytic mouthwash(10ml – 4.8 – 5% traxenamic acid)
7. Should exercise caution prescribing antibiotics and analgesic
medication.

81. 81
 Antibiotics – pencillin, erythromycin, tetracycline, metronidazole,
cephalosporins, ampicillin & amoxicillin + clavulinic acid potentiate the
coumarin action.
 Clindamycin – antibiotic of choice.
 Acetaminophen – interact with coumarin
Use is limited

82. 82
CONCLUSION:
 Dental management of patients with bleeding disorders should be
accomplished in consultation with patient’s physician.
 Most patients with mild to moderate bleeding or clotting problems can be
safely treated in the dental office using local measures, provided there is
proper planning, preparation and a judicious surgical technique.

83. REFERENCES:
 Essentials of physiology. Sembulingam 6th ed
 Textbook of Medical physiology. GuytonHall 12th ed
 Vassilopoulos P, Palcanis K. Bleeding disorders and periodontology. Periodontol 2000.
2007;44:211-23.
 Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth 2014;58:515-
23.
 Coagulation and BloodTransfusion. (The role of calcium in coagulation and anticoagulation
M.E. Mikaelsson 29-39). C.Th.Smit Sibinga, P.C.Das, P.M.Mannucci.
 Gupta A, Epstein JB, Cabay RJ. Bleeding disorders of importance in dental care and related
patient management. J Can Dent Assoc. 2007 Feb;73(1):77-83.
 Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem.2000 83