Hemostasis of blood

• Hemostasis is a precisely orchestrated process involving
platelets, clotting factors, and endothelium that occurs at the
site of vascular injury and culminates in the formation of a
blood clot, which serves to prevent or limit the extent of
bleeding.
• Four major physiologic events participate in the hemostatic
process: vascular constriction, platelet plug formation,
fibrin formation, and fibrinolysis.
• Although each tends to be activated in order, the four
processes are interrelated so that there is a continuum and
multiple reinforcements.

Vascular constriction
• Arteriolar vasoconstriction occurs immediately and markedly
reduces blood flow to the injured area.
• The contraction results from--------
 local myogenic spasm.
 local autacoid factors from the traumatized tissues and blood
platelets.
 nervous reflexes. (The nervous reflexes are initiated by pain
nerve impulses or other sensory impulses that originate from
the traumatized vessel or nearby tissues.).
• The more severely a vessel is traumatized, the greater the
degree of vascular spasm. The spasm can last for many
minutes or even hours, during which time the processes of
platelet plugging and blood coagulation can take place.

• Thromboxane A2 (TXA2), from platelet membranes and
Endothelin [synthesized by injured endothelium and serotonin
(5-hydroxytryptamine [5-HT]) released during platelet
aggregation ] are potent vasoconstrictors.
• Bradykinin and fibrinopeptides, which are involved in the
coagulation schema, are also capable of contracting vascular
smooth muscle.

Primary hemostasis: the formation of the platelet plug.
• Disruption of the endothelium exposes subendothelial von
Willebrand factor (vWF) and collagen, which promote platelet
adherence and activation.
• Activation of platelets results in a dramatic shape change
(from small rounded discs to flat plates with spiky protrusions
that markedly increased surface area), as well as the release of
secretory granules.
• Within minutes the secreted products recruit additional
platelets, which undergo aggregation to form a primary
hemostatic plug.

Secondary hemostasis: deposition of fibrin
• Tissue factor is also exposed at the site of injury.
• Tissue factor is a membrane-bound procoagulant glycoprotein
that is normally expressed by subendothelial cells in the vessel
wall, such as smooth muscle cells and fibroblasts.
• Tissue factor binds and activates factor VII , setting in motion a
cascade of reactions that culiminates in thrombin generation.
• Thrombin cleaves circulating fibrinogen into insoluble fibrin,
creating a fibrin meshwork, and also is a potent activator of
platelets, leading to additional platelet aggregation at the site of
injury.
• This sequence, referred to as secondary hemostasis,consolidates
the initial platelet plug.

Clot stabilization and resorption.
• Polymerized fibrin and platelet aggregates undergo contraction
to form a solid, permanent plug that prevents further
hemorrhage.
• At this stage, counterregulatory mechanisms (e.g., tissue
plasminogen activator, t-PA) are set into motion that limit
clotting to the site of injury and eventually lead to clot
resorption and tissue repair.

Platelets
• Platelets are disc-shaped anucleate cell fragments that are shed
from megakaryocytes in the bone marrow into the bloodstream.
• Platelets play a critical role in hemostasis by forming the primary
plug that initially seals vascular defects and by providing a surface
that binds and concentrates activated coagulation factors.
• Their function depends on several glycoprotein receptors, a
contractile cytoskeleton, and two types of cytoplasmic granules.
• α-Granules have the adhesion molecule P-selectin on their
membranes and contain proteins involved in coagulation, such as
fibrinogen, coagulation factor V, and vWF, as well as protein
factors that may be involved in wound healing,such as fibronectin,
platelet factor 4 (a heparin-binding chemokine), platelet-derived
growth factor (PDGF), and transforming growth factor-β.

• Dense (or δ) granules contain adenosine diphosphate (ADP) and
adenosine triphosphate, ionized calcium, serotonin, and
epinephrine.
• After a traumatic vascular injury, platelets encounter constituents
of the subendothelial connective tissue, such as vWF and collagen.
On contact with these proteins, platelets undergo a sequence of
reactions that culminate in the formation of a platelet plug.

• Platelet adhesion is mediated largely via interactions with
vWF, which acts as a bridge between the platelet surface
receptor glycoprotein Ib (GpIb) and exposed collagen .
Notably, genetic deficiencies of vWF(von Willebrand disease )
or GpIb (Bernard-Soulier syndrome) result in bleeding
disorders, attesting to the importance of these factors.

• Platelets rapidly change shape following adhesion, being
converted from smooth discs to spiky “sea urchins” with
greatly increased surface area.
• This change is accompanied by alterations in glycoprotein
IIb/IIIa that increase its affinity for fibrinogen, and by the
translocation of negatively charged phospholipids (particularly
phosphatidylserine) to the platelet surface.
• These phospholipids bind calcium and serve as nucleation sites
for the assembly of coagulation factor complexes.
• Secretion (release reaction) of granule contents occurs along
with changes in shape; these two events are often referred to
together as platelet activation.
• Platelet activation is triggered by a number of factors,
including the coagulation factor thrombin and ADP.

• Thrombin activates platelets through a special type of G-
protein coupled receptor referred to as a protease-activated
receptor (PAR), which is switched on by a proteolytic cleavage
carried out by thrombin.
• ADP is a component of dense body granules; thus, platelet
activation and ADP release begets additional rounds of platelet
activation, a phenomenon referred to as recruitment.
• Activated platelets also produce the prostaglandin
thromboxane A2 (TxA2), a potent inducer of platelet
aggregation.
• Aspirin inhibits platelet aggregation and produces a mild
bleeding defect by inhibiting cyclooxygenase, a platelet
enzyme that is required for TxA2 synthesis.

• Platelet aggregation follows their activation.
• The conformational change in glycoprotein IIb/IIIa that occurs
with platelet activation allows binding of fibrinogen, a large
bivalent plasma polypeptide that forms bridges between
adjacent platelets, leading to their aggregation.
• The initial wave of aggregation is reversible, but concurrent
activation of thrombin stabilizes the platelet plug by causing
further platelet activation and aggregation, and by promoting
irreversible platelet contraction.
• Platelet contraction is dependent on the cytoskeleton and
consolidates the aggregated platelets.
• In parallel, thrombin also converts fibrinogen into insoluble
fibrin, cementing the platelets in place and creating the
definitive secondary hemostatic plug.

BLOOD COAGULATION IN
THE RUPTURED VESSEL
• During the 19th century, German pathologist Rudolf Virchow
in 1860 (Nichols & Bowie, 2001) described thrombi (blood
clots) and their tendency to embolize. Platelets were
discovered, and their function was established, along with
discovery of the various components of the coagulation
process.
• These advances led to the classic theory of coagulation
described by Paul Morawitz in 1905 (Morawitz,1958).
• He convincingly assembled 4 “coagulation factors” in his
scheme of coagulation.

• The modern understanding of the biochemical processes of
coagulation began in the 1940s, when Paul Owren (1947)
recognized that a bleeding diathesis in a young woman could
not be explained by the 4-factor concept, positing that she
lacked a fifth coagulation factor in her plasma.
• Throughout the 1940s and 1950s, several more coagulation
factors were discovered.
• Coagulation factors were designated by roman numerals.
• The numeric system that was adopted assigned the number to
the factor according to the sequence of discovery and not to
the point of interaction in the cascade.

• By 1957, the following factors were described:--
 von Willebrand factor (VWF) (von Willebrand, 1931),
 factor (F) V (Owren, 1947)
 FVII (Alexander, Goldstein, Landwehr, & Cook, 1951),
 FVIII (Patek & Stetson, 1936),
 FIX (Aggeler et al., 1952; Briggs et al., 1952; Shulman &
Smith, 1952)
 FXI (Rosenthal, Dreskinoff, & Rosenthal, 1953).

• In the 1960s, 2 independent groups of biochemists introduced a model of
coagulation as a series of steps in which activation of each clotting factor
led to the activation of another, culminating in a burst of thrombin
generation.
• The article proposing the cascade model by Macfarlane (1964) appeared in
the journal Nature and was shortly followed by the waterfall model
reported by Davie and Ratnoff (1964) in the journal Science.
• The “cascade” and “waterfall” models suggested that the clotting sequences
were divided into 2 pathways.
• Coagulation could be initiated via an “intrinsic pathway,” so named
because all the components were present in blood.
• an “extrinsic pathway,” in which the subendothelial cell membrane protein,
tissue factor (TF), was required in addition to circulating components.
• The initiation of either pathway resulted in activation of FX and the
eventual generation of a fibrin clot through a common pathway (Luchtman-
Jones & Broze, 1995).

MECHANISM OF
BLOOD COAGULATION
• More than 50 important substances that cause or affect blood
coagulation have been found in the blood and in the tissues—some
that promote coagulation, called procoagulants, and others that
inhibit coagulation, called anticoagulants
• Whether blood will coagulate depends on the balance between these
two groups of substances.
• In the blood stream, the anticoagulants normally predominate, so the
blood does not coagulate while it is circulating in the blood vessels.
However, when a vessel is ruptured, procoagulants from the area of
tissue damage become “activated” and override the anticoagulants,
and then a clot does develop.

• Clotting takes place in three essential steps:
 In response to rupture of the vessel or damage to the blood itself, a
complex cascade of chemical reactions occurs in the blood
involving more than a dozen blood coagulation factors. The net
result is formation of a complex of activated substances collectively
called prothrombin activator.
 The prothrombin activator catalyzes conversion of prothrombin into
thrombin.
 The thrombin acts as an enzyme to convert fibrinogen into fibrin
fibers that enmesh platelets, blood cells, and plasma to form the
clot.

CONVERSION OF PROTHROMBIN
TO THROMBIN

Clot Retraction and Expression of Serum
• Within a few minutes after a clot is formed, it begins to
contract and usually expresses most of the fluid from the clot
within 20 to 60 minutes.
• Platelets are necessary for clot retraction to occur.
• Therefore, failure of clot retraction is an indication that the
number of platelets in the circulating blood might be low.
• Electron micrographs of platelets in blood clots show that they
become attached to the fibrin fibers in such a way that they
actually bond different fibers together.
• platelets entrapped in the clot continue to release procoagulant
substances, one of the most important of which is fibrin-
stabilizing factor, which causes more and more cross-linking
bonds between adjacent fibrin fibers.

• In addition, the platelets contribute directly to clot contraction by
activating platelet thrombosthenin, actin, and myosin molecules,
which are all contractile proteins in the platelets and cause strong
contraction of the platelet spicules attached to the fibrin.
• This action also helps compress the fibrin meshwork into a smaller
mass.
• The contraction is activated and accelerated by thrombin, as well as
by calcium ions released from calcium stores in the mitochondria,
endoplasmic reticulum, and Golgi apparatus of the platelets.
• As the clot retracts, the edges of the broken blood vessel are pulled
together, thus contributing still further to hemostasis

FIBROUS ORGANIZATION OR
DISSOLUTION OF THE BLOOD CLOT
• Once a blood clot has formed, it can follow one of two courses:
 It can become invaded by fibroblasts, which subsequently form
connective tissue all through the clot.
 it can dissolve.
• The usual course for a clot that forms in a small hole of a vessel wall
is invasion by fibroblasts, beginning within a few hours after the clot
is formed (which is promoted at least partially by growth factor
secreted by platelets). This process continues to complete
organization of the clot into fibrous tissue within about 1to 2 weeks.
• Conversely, when excess blood has leaked into the tissues and tissue
clots have occurred where they are not needed, special substances
within the clot itself usually become activated. These substances
function as enzymes to dissolve the clot.

INITIATION OF COAGULATION:
FORMATION OF
PROTHROMBIN ACTIVATOR
• Prothrombin activator is generally considered to be formed in
two ways, although, in reality, the two ways interact constantly
with each other:
 the extrinsic pathway that begins with trauma to the vascular
wall and surrounding tissues.
 the intrinsic pathway that begins in the blood.
• In both the extrinsic and the intrinsic pathways, a series of
different plasma proteins called blood-clotting factors plays a
major role.
• Most of these proteins are inactive forms of proteolytic
enzymes. When converted to the active forms, their enzymatic
actions cause the successive, cascading reactions of the
clotting process.

Interaction between the Extrinsic
and Intrinsic Pathways
• After blood vessels rupture, clotting occurs by both pathways
simultaneously.
• Tissue factor initiates the extrinsic pathway, whereas contact
of Factor XII and platelets with collagen in the vascular wall
initiates the intrinsic pathway.
• the extrinsic pathway once initiated, its speed of completion to
the final clot is limited only by the amount of tissue factor
released from the traumatized tissues and by the quantities of
Factors X, VII, and V in the blood.
• With severe tissue trauma, clotting can occur in as little as 15
seconds.
• The intrinsic pathway is much slower to proceed, usually
requiring 1 to 6 minutes to cause clotting.

The central role of thrombin in hemostasis
• Among the coagulation factors, thrombin is the most
important, in that its various enzymatic activities control
diverse aspects of hemostasis and link clotting to inflammation
and repair.
• Among thrombin’s most important activities are the following:
 Conversion of fibrinogen into crosslinked fibrin.
 Thrombin directly converts soluble fibrinogen into fibrin monomers that
polymerize into an insoluble clot, and also amplifies the coagulation
process, not only by activating factor XI, but also be activating two critical
co-factors, factors V and VIII. It also stabilizes the secondary hemostatic
plug by activating factor XIII, which covalently cross-links fibrin.
 Platelet activation.
 Thrombin is a potent inducer of platelet activation and aggregation through
its ability to activate PARs, thereby linking platelet function to coagulation.

 Pro-inflammatory effects
 PARs are also expressed on inflammatory cells, endothelium, and other cell
types , and activation of these receptors by thrombin is believed to mediate
proinflammatory effects that contribute to tissue repair and angiogenesis.
 Anticoagulant effects
 upon encountering normal endothelium thrombin changes from a
procoagulant to an anticoagulant. This reversal in function prevents clotting
from extending beyond the site of the vascular injury.

Factors That Limit Coagulation.
 Endothelial Surface Factors:
• Platelet inhibitory effects—
 An obvious effect of intact endothelium is to serve as a barrier
that shields platelets from subendothelial vWF and collagen.
 normal endothelium also releases a number of factors that
inhibit platelet activation and aggregation like prostacyclin
(PGI2), nitric oxide (NO), and adenosine diphosphatase; the
latter degradesADP, act as potent activator of platelet
aggregation.
 endothelial cells bind and alter the activity of thrombin, which
is one of the most potent activators of platelets.

• Anticoagulant effects.
 Normal endothelium shields coagulation factors from tissue
factor in vessel walls and expresses multiple factors that
actively oppose coagulation, most notably thrombomodulin,
endothelial protein C receptor, heparin-like molecules, and
tissue factor pathway inhibitor.
 Thrombomodulin and endothelial protein C receptor bind
thrombin and protein C, respectively, in a complex on the
endothelial cell surface.
 When bound in this complex, thrombin loses its ability to
activate coagulation factors and platelets, and instead cleaves
and activates protein C, a vitamin K–dependent protease that
requires a cofactor, protein S.
 Activated protein C/protein S complex is a potent inhibitor of
coagulation factors Va and VIIIa.

 Heparin-like molecules on the surface of endothelium bind and
activate antithrombin III, which then inhibits thrombin and
factors IXa, Xa, XIa, and XIIa.
 Tissue factor pathway inhibitor (TFPI), like protein C, requires
protein S as a cofactor and, as the name implies, binds and
inhibits tissue factor/factor VIIa complexes.
• Fibrinolytic effects.
 Normal endothelial cells synthesize t-PA, act as a key
component of the fibrinolytic pathway.

Activation of Plasminogen to Form Plasmin
• The plasma proteins contain a euglobulin called
plasminogen (or profibrinolysin) that, when activated,
becomes a substance called plasmin (or fibrinolysin).
• The injured tissues and vascular endothelium very slowly
release a powerful activator called tissue plasminogen
activator (t-PA); a few days later, after the clot has
stopped the bleeding, t-PA eventually converts
plasminogen to plasmin, which in turn removes the
remaining unnecessary blood clot.
• Plasmin digests fibrin fibers and some other protein
coagulants such as fibrinogen, Factor V, Factor VIII,
prothrombin, and Factor XII.
• important function of the plasmin system is to remove
minute clots from millions of tiny peripheral vessels that
eventually would become occluded were there no way to
clear them.

Laboratory Tests
• BLEEDING TIME----
• The Ivy bleeding time (BT) has been used to screen for
disorders of platelet function and thrombocytopenia.
• Normal value --1 to 6 minutes.
• The platelet function analyzer (PFA- 100), an instrument that
measures platelet-dependent coagulation under flow
conditions, is more sensitive and specific for platelet disorders
and von Willebrand disease (vWD) than the bleeding time.
• however, it is not sensitive enough to rule out underlying mild
bleeding disorders. Also, it has not been evaluated
prospectively to determine its utility in predicting bleeding
risk, although such studies are underway.
• Therefore, the BT and PFA-100 are not recommended as
screening tests to be used by the dentist

• CLOTTING TIME----
• The one most widely used is to collect blood in a chemically
clean glass test tube and then to tip the tube back and forth
about every 30 seconds until the blood has clotted.
• By this method, the normal clotting time is 6 to 10 minutes.
• Unfortunately, the clotting time varies widely, depending on
the method used for measuring it, so it is no longer used in
many clinics.
• Screening Tests:----
• Three tests are recommended for use in initial screening for
possible bleeding disorders. activated partialthromboplastin
time (aPTT), prothrombin time (PT), and platelet count .
• An additional test can be added to the initial screen: the
thrombin time (TT).

• Partial Thromboplastin Time—
• Partial thromboplastin time (PTT) is used to check the intrinsic
system (factors VIII, IX, XI, and XII) and the common
pathways (factors V and X, prothrombin, and fibrinogen).
• It also is the best single screening test for coagulation
disorders.
• A phospholipid platelet substitute is added to the patient’s
blood to initiate the coagulation process via the intrinsic
pathway. When a contact activator, such as kaolin, is added,
the test is referred to as activated PTT (aPTT).
• In general, aPTT ranges from 25 to 35 seconds, and results in
excess of 35 seconds are considered abnormal or prolonged.
• The aPTT is prolonged in cases of mild to severe deficiency of
factor VIII or IX.

• Prothrombin Time—
• The prothrombin time (PT) is used to check the extrinsic
pathway (factor VII) and the common pathway (factors V and
X, prothrombin, and fibrinogen).
• For this test, tissue thromboplastin is added to the test sample
to serve as the activating agent.
• In general, the normal range is 11 to 15 seconds.
• When the test is used to evaluate the level of anticoagulation
with coumarin-like drugs the INR format is recommended.
• The normal range for INR in a healthy person is 0.9 to 1.3.
• The recommended INR goal for a patient on low-intensity
warfarin therapy is 2.5, with a range of 2.0 to 3.

• Platelet Count---
• Platelet count is used to screen for possible bleeding
problems due to thrombocytopenia.
• Normal platelet count is 140,000 to 400,000/μL of blood.
• Patients with a platelet count of between 50,000 and
100,000/μL manifest excessive bleeding only with severe
trauma.
• Patients with counts below 50,000/μL demonstrate skin and
mucosal purpura and bleed excessively with minor trauma.
• Patients with platelet counts below 20,000/μL may experience
spontaneous bleeding.

• Thrombin Time—
• In this test, thrombin is added to the patient’s blood sample as
the activating agent. It converts fibrinogen in the blood to
insoluble fibrin, which makes up the essential portion of a
blood clot.
• This test bypasses the intrinsic, extrinsic, and most of the
common pathway.
• For example, patients with hemophilia A or factor V deficiency
have a normal TT.
• Generally, the normal range for the TT test is 9 to 13 seconds,
and results in excess of 16 to 18 seconds are considered
abnormal or prolonged.
• Abnormal test results usually are caused by excessive plasmin
or fibrin split products.

CONGENITAL FACTOR DEFICIENCIES
• Hemophilia A---
• The hemostatic abnormality in hemophilia A is caused by a
deficiency or a defect of factor VIII.
• Factor VIII was thought to be produced by endothelial cells
and not by the liver, as most coagulation factors are.
• Hemophilia A is inherited as an X-linked recessive trait. The
defective gene is located on the X chromosome (F8 gene).
• Hemophilia A can manifest in women.
• Normal homeostasis requires at least 30% factor VIII activity.
• Severe forms of the disease occur when the level is less than
1% of normal.
• Clinical Findings---
• Patients with severe hemophilia (less than 1% of factor VIII)
may experience severe, spontaneous bleeding.

• Hemarthrosis, ecchymoses, and soft tissue hematomas are
common.
• Spontaneous bleeding from the mouth, gingiva, lips, tongue,
and nose may occur in these patients.
• This bleeding may be massive and life-threatening, or it may
persist as a slow, continuous oozing for days, weeks, or
months.
• Laboratory Tests---Screening tests that show prolonged aPTT,
normal PT, and normal platelet count (except in some cases of
von Willebrand disease) indicate a problem in the intrinsic
pathway

Hemophilia B.
• In hemophilia B (Christmas disease), factor IX is deficient or
defective.
• Hemophilia B is inherited as an X-linked recessive trait (F9
gene).
• Similar to hemophilia A, the disorder manifests primarily in
males.
• Clinical manifestations of the two disorders are identical.
Screening laboratory test results are similar for both diseases.
• Specific factor assays for factor IX establish the diagnosis.
• Purified factor IX products are recommended for the
treatment of minor and major bleeding

von Willebrand Disease.
• The most common inherited bleeding disorder is von
Willebrand disease, which is caused by an inherited defect
involving platelet adhesion.
• The cause of platelet dysfunction in von Willebrand disease is
a deficiency or a qualitative defect in vWF, which is made
from a group of glycoproteins produced by megakaryocytes
and endothelial cells.
• They are formed into a single monomer that polymerizes into
huge complexes, which are needed to carry (bind) factor VIII
and to allow platelets to adhere to surfaces. Unbound factor
VIII is destroyed in the circulation.
• Most of the variants are transmitted as autosomal dominant
traits (types 1 and 2).
• Type 1 is the most common form of von Willebrand disease. It
accounts for about 70% to 80% of the cases.

• Clinical Findings----
• Mild variants of von Willebrand disease are characterized by a
history of cutaneous and mucosal bleeding because platelet adhesion
is lacking.
• In the more severe forms of the disease, in which factor VIII levels
are low, hemarthroses and dissecting intramuscular hematomas are
part of the clinical picture.
• Serious bleeding can occur in these patients after trauma or surgical
procedures.
• Laboratory Tests---
• Screening laboratory tests may show prolonged aPTT, normal or
slightly reduced platelet count, normal PT, and normal TT.
• Additional laboratory tests are needed to establish the diagnosis and
type of von Willebrand disease.
• These consist of ristocetin cofactor activity, ristocetin-induced
platelet aggregation, immunoassay of vWF, multimeric analysis of
vWF, and specific assays for factor VIII.

 Factor XI Deficiency---
• Factor XI deficiency, an autosomal recessive inherited condition
sometimes referred to as hemophilia C, is more prevalent in the
Ashkenazi Jewish population but found in all races.
• Spontaneous bleeding is rare, but bleeding may occur after surgery,
trauma, or invasive procedures.
 Deficiency of Factors II (Prothrombin), V, and X----
• These deficiencies are inherited as autosomal recessive.
• Treatment of bleeding in individuals with the combined deficiency
requires factor VIII concentrate and FFP.
• Some patients with factor V deficiency are also lacking the factor V
normally present in platelets and may need platelet transfusions as
well as FFP.

• Factor VII Deficiency---
• Inherited factor VII deficiency is a rare autosomal recessive
disorder.
• Bleeding is uncommon unless the level is less than 3%.
• The most common bleeding manifestations involve easy bruising
and mucosal bleeding, particularly epistaxis or oral mucosal
bleeding.
• Treatment is with FFP or recombinant factor VIIa.
• Factor XIII Deficiency----
• Congenital factor XIII (FXIII) deficiency, originally recognized by
Duckert in 1960, is a rare autosomal recessive disease usually
associated with a severe bleeding diathesis.
• Bleeding is typically delayed because clots form normally but are
susceptible to fibrinolysis.
• Umbilical stump bleeding is characteristic, and there is a high risk of
intracranial bleeding.
• Replacement can be accomplished with FFP, cryoprecipitate, or a
factor XIII concentrate.

Platelet Functional Defects
• Inherited platelet functional defects include abnormalities of
platelet surface proteins, abnormalities of platelet granules,
and enzyme defects.
• The major surface protein abnormalities are
thrombasthenia(Glanzmann thrombasthenia) and Bernard-
Soulier syndrome.
• the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex is either
lacking or present but dysfunctional. This defect leads to faulty
platelet aggregation and subsequent bleeding.
• Transfusion of normal platelets is required for bleeding in
these patients.

Qualitative Platelet Defects
• Impaired platelet function often accompanies
thrombocytopenia but may also occur in the presenced of a
normal platelet count.

Management of periodontal
patients with bleeding disorders
• Pre-operative precautions
 A detailed medical history must include the following
 Previous hemorrhagic episodes after trauma or surgery, or even
spontaneous bleeding.
 Family history regarding hereditary bleeding disorders.
 Current illnesses, such as hepatic and renal failure, and a list of
medications interfering with hemostasis, such as nonsteroidal anti-
inflammatory drugs and antibiotics.
 Anticoagulation medications, such as coumarin, heparin, aspirin,
clopidogrel, and ticlodipine.
 Pre-operative care of patients on anticoagulant therapy with
coumarin involves the continuation, reduction or withdrawal of the
medication.
The decision should be based on the international normalized ratio
value, the invasiveness and extent of dental procedure, current illnesses
and medications (Scully C, Wolff A. 2002).

• When the international normalized ratio is<<3.5, periodontal surgical
procedures can be carried out on these patients in a dental office (Little JW
et al 2002, Lockhart PB et al 2003, Scully C et al 2002).
• When the international normalized ratio is >3.5, the anticoagulation
regimen has to be adjusted.
• A safe approach entails reduction of the coumarin dose 2–3 days before the
procedure and repetition of international normalized ratio testing the
morning of the procedure to ensure that the value is <4 (Little JW et al
2002, Lockhart PB et al 2003, Scully C et al 2002).
• International normalized ratio therapeutic levels for most medical
conditions range between 2.5 and 3.5 (Beirne OR, Koechler JR 1996).
• Extensive and invasive periodontal surgical procedures in such patients
should be performed in a hospital setting, and intravenous unfractionated
heparin should be given as a substitute for coumarin 4–6 hours before the
surgical procedure (Scully C et al 2002).
• Patients taking aspirin should discontinue the medication at least 3 days,
and up to 7 days, before the surgical procedure .

• The dental professional may decide if modification of the
anticoagulant regimen will place the patient at risk for a
thromboembolic event .
• In addition, the care of patients with bleeding disorders must be
placed into new perspective. Preventive dental care for patients with
known bleeding disorders has to be intensive and should include
regular dental visits, frequent professional tooth cleanings, oral
hygiene reinforcement, fluoride supplements and mouthrinses, a
low-sugar diet and annual radiographic examination.
• Continued efforts to prevent dental diseases, and arresting dental
diseases at the initial stage, eliminate the need for invasive dental
procedures and reduce the risk of associated prolonged bleeding.
• Patients with diagnosed congenital bleeding disorders should consult
their hematologist before any treatment is rendered.

Intra-operative actions
• minor surgery, involving soft tissues, can be performed with platelet
counts as low as 30,000/μl(Henderson JM et al 2001).
• In mild and moderate inherited coagulopathies, desmopressin or 1-
desamino-8-D arginine vasopressin can be useful.
• Professional cleaning, and scaling and root planing, can be safely
performed with the use of local antifibrinolytic mouthwash, such as
tranexamic acid or epsilon aminocaproic acid (little JW et al 2002)).
• Regional block anesthesia must be avoided.
• Another way to prevent excessive bleeding is the meticulous
handling of soft tissues. Creating a conservative flap design and
minimizing flap elevation are key points.
• Application of pressure for 10 minutes with moistened gauze on the
flap has been suggested (Scully C , Wolff A 2002).
• At the end of surgery, patients susceptible to bleeding are instructed
to bite on a moistened gauze, or gauze soaked with the hemostatic
agent, for 30 minutes.

• After 30 minutes, the gauze is removed and the surgical area is
observed for oozing. If bleeding occurs, additional measures are
initiated. The surgical area is re-entered and the bleeding source is
identified.
• Electrocautery and laser are used to control bleeding in the soft
tissues.
• When oozing arises from hard tissues, bone burnishing and bone
wax are the treatments of choice.
• There are a number of commercially available local hemostatic
agents that enhance clot stabilization. These include: absorbable
gelatin; absorbable collagen; microfibrillar collagen and collagen
dressings ; oxidized regenerated cellulose , thrombin, tranexamic
acid and epsilon-aminocaproic acid ; fibrin glue; and platelet-rich
plasma .
• Collagen, gelatin and cellulose products provide the scaffold for
platelets to adhere to one another and form the platelet plug

Postoperative measures
• Rinsing is prohibited on the day of surgery and the healing site must
be left undisturbed.
• The use of antifibrinolytic mouthwash is highly recommended the
day after periodontal treatment.
• The regimen may comprise rinsing with 10 ml of 4.8–5%tranexamic
acid solution, four times a day, for 2 minutes. The rinsing can be
carried out over a period of 2–5 days and may be extended up to 8
days (Franchini M et al 2005).
• Antibiotics, such as penicillin, erythromycin, tetracycline,
metronidazole, cephalosporins, ampicillin and amoxicillin +
clavulanic acid, potentiate the coumarin action (Herman WW et al
1997, Scully C , Wolff A 2002).
• Acetaminophen can also interact with coumarin and its use must be
limited to fewer than six tablets per week (Scully C , Wolff A 2002).

Hemostasis of blood

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