Coagulation of blood and bleeding disorders

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.
Thirteen clotting factors are identified:
Factor I-Fibrinogen
Factor II- Prothrombin
Factor III- Thromboplastin (Tissue factor)
Factor IV-Calcium
Factor V-Labile factor (Proaccelerin or accelerator globulin)
Factor VI-Presence has not been proved
Factor VII-Stable factor
Factor VIII-Antihemophilic factor (Antihemophilic globulin)
COAGULATION OF BLOOD

Factor IX- Christmas factor
Factor X -Stuart-Prower factor
Factor XI -Plasma thromboplastin antecedent
Factor XII-Hageman factor (Contact factor)
Factor XIII - Fibrin-stabilizing factor.
SEQUENCE OF CLOTTING MECHANISM:
ENZYME CASCADE THEORY:
Most of the clotting factors are proteins in the form of enzymes. Normally, all the factors
are present in the form of inactive proenzyme. These proenzymes must be activated into
enzymes to enforce clot formation. It is carried out by a series of proenzyme-enzyme
conversion reactions. First one of the series is converted into an active enzyme that
activates the second one, which activates the third one; this continues till the final active
enzyme thrombin is formed.
Enzyme cascade theory explains how various reactions, involved in the conversion of
proenzymes to active enzymes take place in the form of a cascade. Cascade refers to a
process that occurs through a series of steps, each step initiating the next, until the final
step is reached.

HEMOSTASIS
Hemostasis is defined as arrest or stoppage of bleeding.
INJURY TO THE BLOOD VESSEL AND DAMAGE TO ENDOTHELIUM
EXPOSURE OF COLLAGEN
ADHERENCE OF PLATELETS TO COLLAGEN
ACTIVATION OF PLATELETS
SECRETION OF
SEROTONIN
VASOCONSTRICTION
FORMATION OF
PROTHROMBIN
ACTIVATOR
SECRETION OF ADP AND
THROMBOXANE A2
AGGREGATION OF
PLATELETS
PLATELET PLUG
FORMATION
BLOOD CLOTTING
VWF
PAF

PATHOPHYSIOLOGY OF BLEEDING AND CLOTTING DISORDERS
A. VASCULAR PHASE:
After tissue injury, there is an immediate reﬂex vasoconstriction that may
alone be hemostatic in small vessels. Reactants such as serotonin,
histamine, prostaglandins and other materials are vasoactive and produce
vasoconstriction of the microvascular bed in the area of the injury.

B. PLATELET PHASE:
• When circulating platelets are exposed to damaged vascular surfaces (in the presence of
functionally normal vWF, endothelial cells, collagen or collagen-like materials, basement
membrane, elastin, microfibrils, and other cellular debris), platelets are activated to experience
physical and chemical changes. These changes produce an environment that causes the platelets
to undergo the aggregation-and-release phenomenon and form the primary vascular plug that
reduces blood loss from small blood vessels and capillaries. These platelet plugs adhere to
exposed basement membranes.
As this reaction is occurring, the release reaction is underway, involving
the intracellular release of active components for further platelet aggregation as well as promotion
of the clotting mechanism. Adenosine diphosphate (ADP) is a potent nucleotide that activates and
recruits other platelets in the area, immensely adding to the size of the plug. Platelet factor 3 (PF3)
is the intracellular phospholipid that activates Factor X and subsequently results in the conversion of
prothrombin to thrombin. Additionally, the platelet plug, intermixed with fibrin and cellular
components such as red and white cells, contracts to further reduce blood loss and to seal the
vascular bed.

C. COAGULATION PHASE:
• The generation of thrombin and ﬁbrin the end product of the third phase of
hemostasis, the coagulation phase. This process involves multiple proteins, many of
which are synthesized by the liver (ﬁbrinogen, prothrombin, Factors
V,VII,IX,X,XI,XII,and XIII) and are vitamin K dependent (Factors II,VII,IX,and X). The
process of coagulation essentially involves three separate pathways. It initially
proceeds by two separate pathways (intrinsic and extrinsic) that converge by activating
a third (common) pathway.

STAGES OF BLOOD CLOTTING
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
Blood clotting commences with the formation of a substance called prothrombin activator,
which converts prothrombin into thrombin. Its formation is initiated by substances
produced either within the blood or outside the blood.
Thus, formation of prothrombin activator occurs through two pathways: i. Intrinsic
pathway ii. Extrinsic pathway.
i. INTRINSIC PATHWAY FOR THE FORMATION OF PROTHROMBIN ACTIVATOR:
In this pathway, the formation of prothrombin activator is initiated by platelets, which are
within the blood itself.

SEQUENCE OF EVENTS IN INTRINSIC PATHWAY:
i. During the injury, the blood vessel is ruptured. Endothelium is damaged and collagen
beneath the endothelium is exposed.
ii. When factor XII (Hageman factor) comes in contact with collagen, it is converted into
activated factor XII in the presence of kallikrein and high molecular weight (HMW) kinogen.
iii. The activated factor XII converts factor XI into activated factor XI in the presence of
HMW kinogen.
iv. The activated factor XI activates factor IX in the presence of factor IV (calcium).
v. Activated factor IX activates factor X in the presence of factor VIII and calcium.
vi. When platelet comes in contact with collagen of damaged blood vessel, it gets activated
and releases phospholipids.
vii. Now the activated factor X reacts with platelet phospholipid and factor V to form
prothrombin activator. This needs the presence of calcium ions.
viii. Factor V is also activated by positive feedback effect of thrombin.

II. EXTRINSIC PATHWAY FOR THE FORMATION OF PROTHROMBIN ACTIVATOR:
In this pathway, the formation of prothrombin activator is initiated by the tissue
thromboplastin, which is formed from the injured tissues.
Sequence of Events in Extrinsic Pathway:
i. Tissues that are damaged during injury release tissue thromboplastin (factor III).
Thromboplastin contains proteins, phospholipid and glycoprotein, which act as proteolytic
enzymes.
ii. Glycoprotein and phospholipid components of thromboplastin convert factor X into
activated factor X, in the presence of factor VII.
iii. Activated factor X reacts with factor V and phospholipid component of tissue
thromboplastin to form prothrombin activator. This reaction requires the presence of
calcium ions

STAGE 2: CONVERSION OF PROTHROMBIN INTO THROMBIN:
Blood clotting is all about thrombin formation. Once thrombin is formed, it definitely leads
to clot formation.
Sequence of Events in Stage 2:
i. Prothrombin activator that is formed in intrinsic and extrinsic pathways converts
prothrombin into thrombin in the presence of calcium (factor IV).
ii. Once formed thrombin initiates the formation of more thrombin molecules. The initially
formed thrombin activates Factor V. Factor V in turn accelerates formation of both extrinsic
and intrinsic prothrombin activator, which converts prothrombin into thrombin. This effect
of thrombin is called positive feedback effect

STAGE 3: CONVERSION OF FIBRINOGEN INTO FIBRIN:
The final stage of blood clotting involves the conversion of fibrinogen into fibrin by
thrombin.
Sequence of Events in Stage 3:
i. Thrombin converts inactive fibrinogen into activated fibrinogen due to loss of 2 pairs of
polypeptides from each fibrinogen molecule. The activated fibrinogen is called fibrin
monomer.
ii. Fibrin monomer polymerizes with other monomer molecules and form loosely arranged
strands of fibrin.
iii. Later these loose strands are modified into dense and tight fibrin threads by fibrin-
stabilizing factor (factor XIII) in the presence of calcium ions. All the tight fibrin threads are
aggregated to form a meshwork of stable clot.

4.FIBRINOLYTIC PHASE
Lysis of blood clot inside the blood vessel
is called fibrinolysis. It helps to remove
the clot from lumen of the blood vessel.
This process requires a substance called
plasmin or fibrinolysin.

BLOOD CLOT:
DEFINITION AND COMPOSITION OF CLOT:
Blood clot is defined as the mass of coagulated blood which contains RBCs, WBCs and
platelets entrapped in fibrin meshwork. RBCs and WBCs are not necessary for clotting
process.
However, when clot is formed, these cells are trapped in it along with platelets. The
trapped RBCs are responsible for the red color of the clot. The external blood clot is also
called scab. It adheres to the opening of damaged blood vessel and prevents blood loss.
CLOT RETRACTION:
After the formation, the blood clot starts contracting. And after about 30 to 45 minutes, the
straw-colored serum oozes out of the clot. The process involving the contraction of blood
clot and oozing of serum is called clot retraction. Contractile proteins, namely actin, myosin
and thrombosthenin in the cytoplasm of platelets are responsible for clot retraction.

• CLASSIFICATION OF BLEEDING DISORDERS
VESSEL WALL DISORDERS:
Vessel wall disorders can result in hemorrhagic features. Bleeding is usually mild and confined
to the skin, mucosa and gingiva. Vascular purpura can result from damage to capillary
endothelium from abnormalities in the vascular subendothelial matrix or extravascular
connective tissue bed, or from abnormal vessel formation. The pathogenesis of bleeding is not
well defined in many conditions, and the capillary fragility test is the only test to demonstrate
abnormal results.
1.SCURVEY:
• Many of the hemorrhagic features of scurvy result from defects in collagen synthesis.
Vitamin C is necessary for the synthesis of hydroxyproline, an essential constituent of
collagen. One of the first clinical signs is petechial hemorrhages at the hair follicles and
purpura on the back of the lower extremities that coalesce to form ecchymoses.
Hemorrhage can occur in the muscles,joints,nail beds, and gingival tissues. Gingival
involvement may include swelling, friability, bleeding, secondary infection and loosening of
teeth. Scurvy results when dietary vitamin C falls below 10 mg/d.

2.CUSHING’S SYNDROME:
Cushing’s syndrome resulting from excessive exogenous or endogenous corticosteroid intake
or production, leads to general protein wasting and atrophy of supporting connective tissue
around blood vessels. Patients may show skin bleeding or easy bruising. Aging causes similar
perivascular connective tissue atrophy and lack of skin mobility. Tears in small blood vessels
can result in irregularly shaped purpuric areas on arms and hands called purpura senilis.
3.EHLER’S DANLOS SYNDROME:
Ehlers-Danlos syndrome is an inherited disorder of connective-tissue matrix, generally
resulting in fragile skin blood vessels and easy bruising. It is characterized by hyperelasticity of
the skin and hypermobile joints. Eleven subtypes have been identiﬁed with unique biochemical
defects and varying clinical features.
Children with type VII syndrome may present with microdontia and
collagen-related dentinal structural defects in primary teeth, in addition to bleeding after tooth
brushing. Other oral ﬁndings include fragility of the oral mucosa, gingiva and teeth as well as
hypermobility of the temporomandibular joint, and stunted teeth and pulp stones on dental
radiographs.

• PLATELET DISORDERS
Platelet disorders may be divided into two categories by etiology—congenital and acquired—and into two
additional categories by type—thrombocytopenias and thrombocytopathies. Thrombocytopenias occur when
platelet quantity is reduced and are caused by one of three mechanisms: decreased production in the bone
marrow, increased sequestration in the spleen or accelerated destruction. Thrombocytopathies, or qualitative
platelet disorders, may result from defects in any of the three critical platelet reactions: adhesion, aggregation,
or granule release. Dysfunctional platelet mechanisms may occur in isolated disorders or in conjunction with
dysfunctional coagulation mechanisms.
• CLASSIFICATION OF PLATELET DISORDERS:
CONGENITAL
-Thrombocytopenic—quantitative platelet deﬁciency
• May-Hegglin anomaly
• Wiskott-Aldrich syndrome
• Neonatal alloimmune thrombocytopenia
-Nonthrombocytopenic—qualitative or functional platelet defect
• Glanzmann’s thrombasthenia
• Platelet-type von Willebrand’s disease
• Bernard-Soulier syndrome

• ACQUIRED
-Thrombocytopenic—quantitative platelet deﬁciency
• Autoimmune or idiopathic thrombocytopenia purpura
• Thrombotic thrombocytopenia purpura
• Cytotoxic chemotherapy
• Drug-induced (eg, quinine, quinidine, gold salts, trimethoprim/ sulfamethoxazole, rifampin)
• Leukemia
• Aplastic anemia
• Myelodysplasia
• Systemic lupus erythematosus
• Associated with infection: HIV, mononucleosis, malaria
• Disseminated intravascular coagulation

-Nonthrombocytopenic—qualitative or functional platelet defect
Drug-induced (eg, by aspirin, NSAIDs, penicillin, cephalosporins) , Uremia
Alcohol dependency, Liver disease
Myeloma, myeloproliferative disorders, macroglobulinemia
Acquired platelet-type von Willebrand’s disease
• COAGULATION DISORDERS
Coagulation disorders may be either congenital or acquired secondary to drugs or disease
processes.
CONGENITAL: Hemophilia A
Hemophilia B
Factor XI, XII,X,V,XIII, I, Von- Willebrand’s disease
ACQUIRED: Secondary to drugs (Heparin, Coumarin) or diseases
(Liver disease, Vitamin K deficiency, DIC)

ANTICLOTTING MECHANISM IN THE BODY:
Under physiological conditions, intravascular clotting does not occur. It is because of the
presence of some physicochemical factors in the body.
1.Physical Factors:
i. Continuous circulation of blood.
ii. Smooth endothelial lining of the blood vessels.
2. Chemical Factors – Natural Anticoagulants
i. Presence of natural anticoagulant called heparin that is produced by the liver
ii. Production of thrombomodulin by endothelium of the blood vessels (except in brain
capillaries). Thrombomodulin is a thrombin-binding protein. It binds with thrombin and
forms a thrombomodulin-thrombin complex. This complex activates protein C. Activated
protein C along with its cofactor protein S inactivates Factor V and Factor VIII. Inactivation
of these two clotting factors prevents clot formation.
iii. All the clotting factors are in inactive state.

ANTICOAGULANTS:
Substances which prevent or postpone coagulation of blood are called anticoagulants.
Anticoagulants are of three types:
1. Anticoagulants used to prevent blood clotting inside the body, i.e. in vivo.
2. Anticoagulants used to prevent clotting of blood that is collected from the body, i.e. in
vitro.
3. Anticoagulants used to prevent blood clotting both in vivo and in vitro.
Ex: Heparin, Coumarin derivatives, EDTA, Oxalate compounds, Citrates.

1.HEPARIN:
• Naturally produced anticoagulant in the body.
• Produced by mast cells which are the wandering cells present immediately outside the
capillaries in many tissues or organs that contain more connective tissue.
• These cells are abundant in liver and lungs.
• Basophils also secrete heparin.
MECHANISM OF ACTION OF HEPARIN:
i. Prevents blood clotting by its antithrombin activity. It directly suppresses the activity of
thrombin
ii. Combines with antithrombin III (a protease inhibitor present in circulation) and removes
thrombin from circulation
iii. Activates antithrombin III
iv. Inactivates the active form of other clotting factors like IX, X, XI and XII

USES OF HEPARIN:
Heparin is used as an anticoagulant both in vivo and in vitro.
Clinical use:
Intravenous injection of heparin (0.5 to 1 mg/kg body weight) postpones clotting for 3 to 4
hours (until it is destroyed by the enzyme heparinase). So, it is widely used as an
anticoagulant in clinical practice. In clinics, heparin is used for many purposes such as:
i. To prevent intravascular blood clotting during surgery.
ii. While passing the blood through artificial kidney for dialysis.
iii. During cardiac surgery.
iv. To preserve the blood before transfusion.
Use in the laboratory:
Heparin is also used as anticoagulant in vitro while collecting blood for various
investigations. About 0.1 to 0.2 mg is sufficient for 1 mL of blood. It is effective for 8 to 12
hours. After that, blood will clot because heparin only delays clotting and does not prevent
it. Heparin is the most expensive anticoagulant.

2. COUMARIN DERIVATIVES:
Warfarin and dicoumoral are the derivatives of coumarin.
Mechanism of Action: Coumarin derivatives prevent blood clotting by inhibiting the action
of vitamin K. Vitamin K is essential for the formation of various clotting factors, namely II,
VII, IX and X.
Uses:
Dicoumoral and warfarin are the commonly used oral anticoagulants (in vivo). Warfarin is
used to prevent myocardial infarction (heart attack), strokes and thrombosis.

3. EDTA:
Ethylenediaminetetraacetic acid (EDTA) is a strong anticoagulant. It is available in two
forms:
i. Disodium salt (Na2 EDTA). ii. Tripotassium salt (K3 EDTA).
Mechanism of Action:
These substances prevent blood clotting by removing calcium from blood.
Uses :
EDTA is used as an anticoagulant both in vivo and in vitro. It is:
i. Commonly administered intravenously, in cases of lead poisoning.
ii. Used as an anticoagulant in the laboratory (in vitro). 0.5 to 2.0 mg of EDTA per mL of
blood is sufficient to preserve the blood for at least 6 hours. On refrigeration, it can
preserve the blood up to 24 hours.

4. OXALATE COMPOUNDS:
Oxalate compounds prevent coagulation by forming calcium oxalate, which is precipitated
later. Thus, these compounds reduce the blood calcium level. Earlier sodium and potassium
oxalates were used. Nowadays, mixture of ammonium oxalate and potassium oxalate in
the ratio of 3 : 2 is used. Each salt is an anticoagulant by itself. But potassium oxalate alone
causes shrinkage of RBCs. Ammonium oxalate alone causes swelling of RBCs. But together,
these substances do not alter the cellular activity.
Oxalate combines with calcium and forms insoluble calcium oxalate. Thus, oxalate removes
calcium from blood and lack of calcium prevents coagulation.
Uses:
Oxalate compounds are used only as in vitro anticoagulants. 2 mg of mixture is necessary
for 1 ml of blood. Since oxalate is poisonous, it cannot be used in vivo.

5. CITRATES:
Sodium, ammonium and potassium citrates are used as anticoagulants.
Citrate combines with calcium in blood to form insoluble calcium citrate. Like oxalate,
citrate also removes calcium from blood and lack of calcium prevents coagulation.
Uses:
Citrate is used as in vitro anticoagulant. i. It is used to store blood in the blood bank as: a.
Acid citrate dextrose (ACD): 1 part of ACD with 4 parts of blood b. Citrate phosphate
dextrose (CPD): 1 part of CPD with 4 parts of blood ii. Citrate is also used in laboratory in
the form of formol-citrate solution (Dacie’s solution) for RBC and platelet counts.

BLEEDING TIME CLOTTING TIME
Bleeding time (BT) is the time
interval from oozing of blood after a
cut or injury till arrest of bleeding.
Clotting time (CT) is the time interval
from oozing of blood after a cut or
injury till the formation of clot.
Determined by Duke method using
blotting paper or filter paper method
Determined by capillary tube
method.
Normal duration is 3 to 6 minutes Normal duration is 3 to 8 minutes
Prolonged in Purpura. Prolonged in Hemophilia
TESTS FOR BLOOD CLOTTING

PROTHROMBIN TIME:
• Prothrombin time (PT) is the time taken by blood to clot after adding tissue
thromboplastin to it. Blood is collected and oxalated so that, the calcium is precipitated
and prothrombin is not converted into thrombin. Thus, the blood clotting is prevented.
• Then a large quantity of tissue thromboplastin with calcium is added to this blood.
Calcium nullifies the effect of oxalate. The tissue thromboplastin activates prothrombin
and blood clotting occurs.
• During this procedure, the time taken by blood to clot after adding tissue thromboplastin
is determined. Prothrombin time indicates the total quantity of prothrombin present in
the blood.
• Normal duration of prothrombin time is 10 to 12 seconds. It is prolonged in deficiency of
prothrombin and other factors like factors I, V, VII and X. However, it is normal in
hemophilia.

PARTIAL PROTHROMBIN TIME OR ACTIVATED PROTHROMBIN TIME:
• Partial prothrombin time (PPT) is the time taken for the blood to clot after adding an
activator such as phospholipid, along with calcium to it. It is also called activated partial
prothrombin time (APTT).
• This test is useful in monitoring the patients taking anticoagulant drugs. It is carried out
by observing clotting time after adding phospholipid, a surface activator and calcium to a
patient’s plasma. Phospholipid serves as platelet substitute.
• Commonly used surface activator is kaolin.
• Normal duration of partial prothrombin time is 30 to 45 seconds. It is prolonged in
heparin or warfarin therapy (since heparin and warfarin inhibit clotting) and deficiency or
inhibition of factors II, V, VIII, IX, X, XI and XII.

THROMBIN TIME:
Thrombin time (TT) 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. This test involves observation of clotting
time after adding thrombin to patient’s plasma. Normal duration of thrombin
time is 12 to 20 seconds. It is prolonged in heparin therapy and during
dysfibrinogenemia (abnormal function of fibrinogen with normal fibrinogen
level).

Bleeding disorders are the conditions characterized by prolonged bleeding time or clotting
time. Bleeding disorders are of three types:
1. Hemophilia. 2. Purpura. 3. von Willebrand disease.
1.HEMOPHILIA is a group of sex-linked inherited blood disorders, characterized by
prolonged clotting time. However, the bleeding time is normal. Usually, it affects the males,
with the females being the carriers.
Because of prolonged clotting time, even a mild trauma causes excess bleeding
which can lead to death. Damage of skin while falling or extraction of a tooth may cause
excess bleeding for few weeks. Easy bruising and hemorrhage in muscles and joints are also
common in this disease.
Causes: Hemophilia occurs due to lack of formation of prothrombin activator. That is why
the coagulation time is prolonged. The formation of prothrombin activator is affected due
to the deficiency of factor VIII, IX or XI.
BLEEDING DISORDERS

Types of hemophilia:
Depending upon the deficiency of the factor involved, hemophilia is classified into three
types:
i. Hemophilia A or classic hemophilia: Due to the deficiency of factor VIII. 85% of people
with hemophilia are affected by hemophilia A.
ii. Hemophilia B or Christmas disease: Due to the deficiency of factor IX. 15% of people
with hemophilia are affected by hemophilia B.
iii. Hemophilia C or factor XI deficiency: Due to the deficiency of factor XI. It is a very rare
bleeding disorder.
Symptoms:
i. Spontaneous bleeding. ii. Prolonged bleeding due to cuts, tooth extraction and surgery.
iii. Hemorrhage in gastrointestinal and urinary tracts. iv. Bleeding in joints followed by
swelling and pain v. Appearance of blood in urine.

Normal levels of factor VIII range from 55 to 100%.
• Severe deficiency: less than 1%
• Moderate deficiency: Levels between 1 to 5 %
• Mild deficiency: Levels greater than or equal to 5% or less than 50%.
Oral findings:
• Mouth lacerations are common cause of bleeding in children with all severities of
anemia.
• Bleeding is also common from Maxillary frenum and tongue.

TREATMENT:
• Replacement of deficiency coagulation factor.
• In the past whole blood, plasma or cryoprecipitate was used; but at present, genetically
engineered products represent the main source of replacement therapy.
HEMOPHILIA A:
• Vials of factor concentrate are labelled with the number of international units contained, where
1IU is the activity of procoagulant in 1 ml of normal plasma.
• For routine haemorrhagic episodes, such as early joint, soft tissue and oral bleeds, an initial
correction to 40 to 50% commonly achieves hemostasis and resolution of bleeding episodes.
• Mild deficiency: DDAVP (1- diamino-8-D-arginine vasopressin) used to achieve hemostasis. This
drug when given IV,SC or Intranasally causes a rise in activity of factor VIII and VWF through
release from stored sites in endothelial cells.
• Peak levels: IV/SC: 1 hr
Intranasally: 90 minutes

HEMOPHILIA B:
• Coagulation factor IX concentrate.
• In the past, prothrombin complex concentrates were used which contained other
vitamin- K dependent factors in addition to factor IX.
TREATMENT REGIMENS:
• Replacement therapy administered after a bleeding episode has occurred ( On- demand
therapy).
• As therapy administered on regularly scheduled basis to prevent or suppress bleeding
episodes ( Prophylaxis).

DEVELOPMENT OF A TREATMENT PLAN:
• The dentist must be aware of the procedures that can be safely performed and those in
which complications may arise.
• The dentist should confer with the patient’s physician and haematologist to formulate an
appropriate treatment plan and discuss the type of anesthetic anticipated to be
administered, invasiveness of the dental procedure, amount of bleeding anticipated and
the time involved in oral wound healing.
• The dentist should know the type of bleeding disorder, severity, frequency and treatment
plan of bleeding episodes.

USE OF ANTIFIBRINOLYTIC AGENTS:
Antifibrinolytic agents are an adjunctive therapy for dental management of patients with
bleeding disorders and are important for the prevention or treatment of oral bleeding.
These agents include ε-aminocaproic acid and tranexamic acid .
Hemophilic patients form loose, friable clots that are easily dislodged or
rapidly dissolved, especially in the oral cavity, where local fibrinolysis is increased.
Antifibrinolytics prevent clot lysis within the oral cavity and are often used as an adjunctive
therapy to factor concentrates.
For some dental procedures in which minimal bleeding is anticipated,
antifibrinolytics may be recommended as the sole hemostatic agent.

DOSAGES:
In children ε-aminocaproic acid is given immediately before dental treatment in
an initial loading dose of 100 to 200 mg/kg by mouth up to a maximum total dose
of 10 g. Subsequently, 50 to 100 mg/kg per dose up to a total maximum dose of 5
g is administered orally every 6 hours for 5 to 7 days. Alternatively, for patients of
approximately adult size or heavier than 30 kg, a regimen of 3 g by mouth 4 times
daily without a loading dose may be used.
The maximum oral dose of tranexamic acid is 25 mg/ kg; for a 60 kg
adult, the dose is 1500 mg every 8 hours. Doses of 10 to 15 mg/kg/kg body
weight have been reported to be effective depending on the location and severity
of bleeding. Dosing is continued every 8 hours for 5 to 7 days

PAIN CONTROL:
Analgesia:
• If patient apprehension is significant, sedation or nitrous oxide–oxygen inhalation
analgesia may be considered.
• Hypnosis has also proved beneficial for some individuals.
• Analgesics containing aspirin or anti-inflammatory agents (e.g., ibuprofen) may affect
platelet function and should be avoided.
• Acute pain of moderate intensity is frequently managed with acetaminophen.
• For severe pain, narcotic analgesics may be required.

Local Anesthesia
• In the absence of factor replacement, periodontal ligament (PDL) injections may be used.
• Infiltration anesthesia can generally be administered without pretreatment with either ε-
aminocaproic acid or replacement therapy. However, if the infiltration injection is into
loose connective tissue or a highly vascularized area, then factor concentrate
replacement to achieve a level of approximately 30% to 40% activity is required.
• One must proceed with caution when considering block anesthesia. The loose,
connective, nonfibrous, and highly vascularized tissue at the sites of inferior alveolar
nerve injection and posterior superior alveolar injections is predisposed to development
of a dissecting hematoma, which may cause airway obstruction and result in a life-
threatening bleeding episode. Therefore a minimum of a 40% factor correction is
mandatory with block anesthesia.
• The dentist must carefully aspirate to ensure that the needle has not entered a blood
vessel. If bloody aspirate is present, further factor replacement may be required

DENTAL MANAGEMENT
Appointments should be arranged so that maximum treatment is accomplished per visit in
order to minimize the need for unscheduled factor infusions and resultant increased cost.
PREVENTION OF DENTAL DISEASE:
• A program that includes toothbrushing, flossing, appropriate topical fluoride exposure,
adequate systemic fluoride administration, consumption of a proper diet, and
professional examination at regular intervals is an effective approach to the prevention
of dental problems.
• Rubber cup prophylaxis and supragingival scaling may be safely performed without prior
factor replacement therapy.
• Minor bleeding is often controlled with local measures, such as direct pressure with a
moistened gauze square. If bleeding persists for several minutes, the topical application
of recombinant thrombin, microfibrillar collagen and local fibrin glue may be of value.

PERIODONTAL THERAPY:
• Patients who require deep scaling due to gross calculus should initially undergo
supragingival scaling. The tissue should be allowed to heal for 7 to 14 days, during which
time the gingiva recedes as edema and hyperemia diminish. Subsequent treatments to
remove calculus and irritants therefore incur decreased bleeding risk from the tissue.
• If subgingival scaling is planned, replacement therapy may be considered, depending on
the amount of anticipated bleeding and the severity of the factor deficiency.
• An abnormal frenum attachment may cause gingival recession and pocket formation.
Early treatment is indicated to prevent continued gingival recession and alveolar bone
loss. All appropriate frenectomy techniques are surgically acceptable for patients with
bleeding disorders; both factor concentrate replacement and antifibrinolytic therapy are
required before frenum or other periodontal surgery.

RESTORATIVE PROCEDURES:
• Patients with bleeding disorders should be allowed to consider all restorative procedures.
• Most restorative procedures on primary teeth are successfully completed, without factor
concentrate replacement, by PDL injections of local anesthesia or local infiltration.
• If a mandibular block or a posterior superior alveolar injection is anticipated, factor
concentrate replacement to a level of 40% and antifibrinolytic therapy are required before
injection.
• Wedges and matrices can be used conventionally. During proximal preparation, the wedge
retracts the papilla, thus protecting it. A properly placed matrix should not cause bleeding.

• High-speed vacuum and saliva ejectors must be used with caution to prevent sublingual
hematomas. Care must also be used in the placement of intraoral radiographic films,
particularly in highly vascular sublingual tissues.
• A rubber dam should be used to isolate the operating field and retract and protect the
cheeks, lips, and tongue. These soft tissues are highly vascular, and accidental laceration
may present a difficult management problem. A thin rubber dam is preferred, since there
is a decreased tendency to torque the rubber dam retainer and cause gingival tissue
abrasion. The retainer should be placed carefully so that it is stable. If a retainer slips, it
may lacerate the gingival papilla. Retainers with subgingival extensions should be
avoided.

PULPAL THERAPY:
• At times pulp exposures in primary and permanent teeth may be avoided if carious
dentin is not entirely removed in one procedure (indirect pulp therapy).
• A pulpotomy or pulpectomy is preferable to extraction. The extraction of a tooth in an
individual with a bleeding disorder involves more complicated treatment and expense.
• Most vital pulpotomy and pulpectomy procedures can be successfully completed with
local infiltration anesthesia. Nitrous oxide–oxygen inhalation analgesia may also help
alleviate discomfort.
• If the pulp of a vital tooth is exposed, an intrapulpal injection may be used safely to
control pain. Bleeding from the pulp chamber does not present a significant problem, in
that it is readily controlled with pressure from cotton pledgets.
• If pulp tissue is necrotic, local anesthetic is usually unnecessary.

ORAL SURGERY:
• For simple extractions of erupted permanent teeth and multirooted primary teeth, a 30% to
40% factor correction is administered within 1 hour before dental treatment. Antifibrinolytic
therapy should be started immediately before or after the procedure and should be
continued for 5 to 10 days. The patient should be placed on a clear liquid diet for the first 72
hours. For the next week, a soft, pureed diet is recommended. During this period, the patient
should not use straws, metal utensils, pacifiers, or bottles. After 10 days the patient may
begin to consume a more normal diet. Specific postoperative instructions should be provided
to the patient and parent. Factor concentrate is extremely costly; therefore all extractions
should be completed in one appointment if possible.

• After extractions are completed, direct topical application of hemostatic agents, such as
thrombin or microfibrillar collagen hemostat may assist with local hemostasis. The socket
should be packed with an absorbable gelatin sponge, microfibrillar collagen or topical
thrombin or fibrin glue may then be placed in the wound. Direct pressure with gauze
should then be applied to the area.
• Stomahesive may be placed over the wound for additional protection from the oral
environment. In general, the use of sutures should be avoided unless suturing is
expected to markedly enhance healing, in which case resorbent sutures are
recommended.

• For surgical extractions of impacted, partially erupted, or unerupted teeth- Factor
replacement + Antifibrinolytic therapy should be started immediately before or after the
procedure and continue for 7 to 10 days.
• For simple extractions of single-rooted primary teeth (i.e., incisors and canines), the
amount of root development present must be evaluated to determine whether factor
replacement therapy is required. If there is complete root development, factor
replacement therapy is likely required, whereas if there is only partial root formation,
antifibrinolytic therapy along with local hemostatic agents may be all that is required.
• The normal exfoliation of primary teeth does not usually result in bleeding or require
factor replacement. Bleeding in these circumstances can generally be controlled with
direct finger and gauze pressure maintained for several minutes. The direct topical
application of an adjunctive agent may also help with local hemostasis. If there is
continuous slow bleeding, antifibrinolytic therapy may be initiated.

ORTHODONTIC TREATMENT:
• Early recognition of an orthodontic problem is important because selective guidance can
diminish or eliminate complex orthodontic problems.
• Both interceptive and full-banded orthodontics may be performed if required. Care must
be taken in the adaptation and placement of bands and in the avoidance of protruding
sharp edges and wires to prevent laceration of oral mucosa.
• Bleeding caused by an accidental scratch or minor laceration of the gingiva usually
responds to applied pressure for 5 minutes.
• The use of preformed orthodontic bands and brackets, which can be bonded directly to
the teeth, almost totally eliminates contact of orthodontic appliances with gingiva during
placement.

2. PURPURA is a disorder characterized by prolonged bleeding time. However, the clotting
time is normal. Characteristic feature of this disease is spontaneous bleeding under the
skin from ruptured capillaries. It causes small tiny hemorrhagic spots in many areas of the
body. The hemorrhagic spots under the skin are called purpuric spots (purple colored patch
like appearance). That is why this disease is called purpura. Blood also sometimes collects
in large areas beneath the skin which are called ecchymoses.
Types: Purpura is classified into three types depending upon the causes:
i. Thrombocytopenic purpura is due to the deficiency of platelets (thrombocytopenia). In
bone marrow disease, platelet production is affected leading to the deficiency of platelets.
ii. Purpura due to some unknown cause is called idiopathic thrombocytopenic purpura. It is
believed that platelet count decreases due to the development of antibodies against
platelets, which occurs after blood transfusion.
iii. Thrombasthenic purpura is due to structural or functional abnormality of platelets.
However, the platelet count is normal. It is characterized by normal clotting time, normal
or prolonged bleeding time but defective clot retraction.

LABORATORY DIAGNOSIS:
• Complete blood count (CBC).:This common
blood test is used to determine the number of
blood cells, including platelets, in a sample of
blood. With ITP, white and red blood cell
counts are usually normal, but the platelet
count is low.

• Blood smear: This test is often used to confirm the number of platelets observed in a
complete blood count. A sample of blood is placed on a slide and observed under a
microscope.
• Bone marrow exam: This test may be used to help identify the cause of a low platelet
count, though the American Society of Hematology doesn't recommend this test for
children with ITP.
• Platelets are produced in the bone marrow — soft, spongy tissue in the center of large
bones. In some cases, a sample of bone tissue and the enclosed marrow is removed in a
procedure called a bone marrow biopsy. Or your doctor may do a bone marrow
aspiration, which removes some of the liquid portion of the marrow. In many cases, both
procedures are performed at the same time (bone marrow exam).
• In people with ITP, the bone marrow will be normal because a low platelet count is
caused by the destruction of platelets in the bloodstream and spleen — not by a
problem with the bone marrow.

• Dental procedures can be performed in patients with platelet counts above 50,000/mm3. In
the need of surgical interventions on a patient whose platelet count is too low, blood
transfusion or previous corticosteroid treatment is deemed necessary according to medical
prescription.
• The surgeon-dentist must avoid trauma to the buccal mucosa by carefully puncturing the
needles, adapting orthodontic braces and avoiding super-activation.
• Prescription of antiplatelet drugs, such as acetylsalicylic acid and ibuprofen, must be avoided.
• Appropriate control of dental biofilm is of the utmost importance, in order to prevent
gingival inflammation and infections. Individual protocols for prevention of caries must be
established according to caries risk and age of each patient.
• If there is the need for restoration treatments, endodontic and surgical treatment,
antibiotics prophylaxis can be performed to reduce the risk of postoperative infections

3. VON WILLEBRAND DISEASE is a bleeding disorder, characterized by excess bleeding even
with a mild injury.
• It is due to deficiency of von Willebrand factor, which is a protein secreted by
endothelium of damaged blood vessels and platelets. This protein is responsible for
adherence of platelets to endothelium of blood vessels during hemostasis after an injury.
It is also responsible for the survival and maintenance of factor VIII in plasma.
• Deficiency of von Willebrand factor suppresses platelet adhesion. It also causes
deficiency of factor VIII. This results in excess bleeding, which resembles the bleeding
that occurs during platelet dysfunction or hemophilia.

• Bleeding gums are often the result of inadequate
plaque removal from the teeth at the gum line.
This usually results in inflammation of the gums
(gingivitis).
• But consistent gum bleeding may indicate a more
serious medical condition, such as leukemia and
the coagulation abnormalities associated with
this disease.
• Other common causes of bleeding gums include
Vitamin deficiencies and medications, especially
blood thinners that have a tendency to have
bleeding gums as a side effect.
BLEEDING GUMS
Symptoms you may notice
with bleeding gums
include:
Gum tenderness
Mouth sores or ulcers
Receding gums
Swollen gums
Bleeding gums may also result
from:
• Brushing too hard
• Vitamin C,K deficiency
• Bleeding disorders such as
Hemophilia, Idiopathic
thrombocytopenic purpura.
• Poor teeth alignment or
positioning
• Infection either gum or tooth
related
• Bacterial, viral infections
• Blood dyscrasias
• Aplastic anemia
• Dry mouth

TESTS FOR BLEEDING GUMS
• Oral examination and X-ray of teeth and gums
• Blood analysis
• Hb%
• Coagulation factors
• Prothrombin time
• Bleeding time
• Clotting time

LOCAL HAEMOSTATICS (STYPTICS) :
• After injury to arterioles and other smaller blood vessels, normal hemostasis occurs successively
by contraction of injured vessel wall (lasting few minutes), adhesion and aggregation of platelets
to form a plug, formation of a blood clot, and finally in due course dissolution of the clot by
fibrinolysis.
• External bleeding is usually stopped by manual pressure, cotton-gauze pressure pack or by
suturing.
• Control of bleeding may be aided by local hemostatics (styptics) that are substances used to stop
bleeding from a local and approachable site. They are particularly effective on oozing surfaces,
e.g. tooth socket, abrasions, etc.
• Absorbable materials like fibrin (prepared from human plasma and dried as sheet or foam),
gelatin foam, oxidized cellulose (as strips which can be cut and placed in the wound) provide a
meshwork which activates the clotting mechanism and checks bleeding.

• Left in situ these materials are absorbed in 1–4 weeks and generally cause no foreign
body reaction.
• Thrombin obtained from bovine plasma may be applied as dry powder or freshly
prepared solution to the bleeding surface in hemophilics.
• Vasoconstrictors like 0.1% Adrenaline solution may be soaked in sterile cotton gauze and
packed in the bleeding tooth socket or nose in case of epistaxis to check bleeding when
spontaneous vasoconstriction is inadequate.
• Astringents such as tannic acid or metallic salts are occasionally applied for bleeding
gums.

Coagulation of blood and bleeding disorders

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