Hemostasis in Dentistry

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vi Contents

10 Review of Anticoagulants������������������������������������������������������������������ 99
David P. Reardon and Christopher Zemaitis
11 Pharmacologic Reversal Agents������������������������������������������������������ 109
James F. Gilmore, Michael J. Schontz, and
Kenneth E. Lupi Jr.

Part III Management of the Dental Patient on

Antithrombotic Therapy

12 Perioperative Management of Dental Patients

on Antiplatelet Medications������������������������������������������������������������ 125
Michael J. Wahl
13 Perioperative Management of Patients on
Anticoagulant Medications: General Principles in
Medicine and Surgery���������������������������������������������������������������������� 143
Jessica Rimsans and Katelyn W. Sylvester
14 Perioperative Management of Dental Patients
on Anticoagulants���������������������������������������������������������������������������� 151
Michael J. Wahl
15 Local Techniques and Pharmacologic Agents
for Management of Bleeding in Dentistry������������������������������������� 187
Richard P. Szumita and Paul M. Szumita

Index�������������������������������������������������������������������������������������������������������� 201
Introduction

Understanding hemostasis is essential for the safe management of patients

undergoing dental treatment. The dental literature has consistently reviewed
topics in hemostasis, particularly in management of patients with pathology
of hemostasis and on medications altering hemostasis. The literature has
detailed time-tested protocols to help with decision-making in the periopera-
tive period. With this literature support and clinical experience, dental clini-
cians, along with their physician colleague input when appropriate, have been
proficient in safely managing patients with disorders of hemostasis.
However, two major categories of changes related to hemostasis have sur-
faced in the recent past. First, evolution of the understanding of hemostasis,
the pathology of hemostasis, and medical advances relating to hemostasis
continue to occur. Second, the number of medications—especially oral medi-
cations—impacting upon hemostasis has been increasing rapidly. These addi-
tional medications are not simply clones of medications that we have all
gained clinical experience in managing—but newer classes of medications
with different pharmacodynamics and varying indications for clinical use.
The “time-tested” clinical guidelines for which clinicians have relied may no
longer be appropriate for the newer classes of medications now being pre-
scribed. In order to safely manage patients, clinicians need to be familiar with
important steps in the hemostatic process and with how the newer drugs
impact hemostasis.
To standardize the information presented throughout this book, a few criti-
cal terms are reviewed. Antithrombotic medications refer to any medications
that cause an effect on the formation and/or maintenance of a thrombus or
clot. Antithrombotic medications include anticoagulants, antiplatelet, and
fibrinolytic medications. Anticoagulants refer to medications reducing the
formation of fibrin from fibrinogen. Antiplatelet medications affect formation
of a platelet plug. Fibrinolytic mediations are “clot” busters used in the hos-
pital environment for the emergency treatment of thromboembolic diseases—
ischemic stroke, myocardial infarction, and acute pulmonary embolism [1].
Patients taking anticoagulant and antiplatelet agents are commonly present-
ing for dental care, and therefore, their review is a primary focus of this work.
Since fibrinolytics are not encountered in dental practice, the discussion of
these agents will be limited.

vii
viii Introduction

Antithrombotics

Antiplatelet
Anticoagulants Fibrinolytics
medications

Although there are slight variations in the definition of hemostasis, a clini-

cal definition that seems apropos for the climate in which we practice is
reflected in the following: Hemostasis is the physiologic system of competent
blood vessels, endothelial cells, platelets, and numerous plasma proteins that
act in a finely controlled manner to preserve blood vessel integrity and pre-
vent pathologic hemorrhage or thrombosis [2]. While surgical disciplines
(including dentistry) strive to prevent excessive hemorrhage during and fol-
lowing procedures, medicine and pharmacology are increasing the number of
medications used to alter hemostasis in order to decrease the morbidity and
mortality associated with inappropriate thrombus formation. Dental clini-
cians should be familiar with contemporary treatment recommendations.
In this book, the physiology and pathophysiology of hemostasis will be
reviewed with emphasis on updated topics. The physiology of hemostasis is
complex. The review provided herein is intended to be of sufficient depth to
allow students, residents, and practicing clinicians in dentistry and the dental
specialties a thorough understanding of the updated models of hemostasis
and the essential steps and reactions responsible for cessation of bleeding
and prevention of excessive thrombus formation. A limited number of patho-
logic alterations in hemostasis will be reviewed in order to contrast normal
physiology. This work will highlight pharmacologic agents that affect hemo-
stasis with emphasis on the expanding number and role of direct oral anti-
thrombotics which will be increasingly prevalent in dental practice. Finally,
evidence-based guidelines are presented to assist the clinician in delivering
safe dental treatment.

References

1. Hamilton R. Tarascon pocket pharmacopoeia: 2015. Burlington, MA:

Jones & Bartlett Publishing; 2015.
2. Macik BG. Hemostasis. In: Moylan JA, editor. Surgical critical care. St.
Louis: Mosby-Year Book, Inc.; 1994. P. 697–718.

Paterson, NJ, USA Paul M. Szumita

Boston, MA, USA Richard P. Szumita
Part I
Review of Hemostasis
Local Tissues in Hemostasis
and Platelet Review
1
Tiffany Kuang and Richard P. Szumita

Abstract thrombosis. With vessel injury, the e­ ndothelium

Hemostasis is a complex physiologic state able and subendothelial tissues are responsible for
to change rapidly depending on the needs of initiating the explosion of pro-hemostatic
the organism. The hemostatic system broadly responses culminating in clotting and cessation
consists of three essential elements: local (vas- of bleeding.
cular) tissues, platelets, and biochemical fac- The second component of hemostasis, the
tors. In health, these three elements maintain a platelet, also fluctuates from neutral to pro-
state of neutrality (or mild antithrombosis) to thrombotic states. With hemorrhage, platelets
prevent pathologic intravascular clotting. become the essential mediators that anchor the
When needed to stop hemorrhage at a site of procoagulant reactions to the site of vascular
injury, the hemostatic system rapidly allows injury, leading to local thrombus formation
for a powerful prothrombotic response at the and the cessation of bleeding.
site of injury while maintaining neutrality This chapter reviews the fundamental
throughout the remainder of the organism. physiology and pathophysiology of local tis-
Maintaining the appropriate state of hemo- sues and platelets in hemostasis. This knowl-
stasis begins with the very tissues in which the edge is essential for understanding diseases
blood circulates—blood vessels. Endothelium, and management of patients with bleeding
which lines the vessels, and subendothelial disorders attributed to local tissues and plate-
structures are physiologically active in hemosta- lets and the pharmacology of current and
sis. When uninjured and in a non-pathologic developing antiplatelet medications.
state, the endothelium allows blood to remain in
a fluid state, preventing pathologic intravascular

Hemostasis is a complex physiologic process that

T. Kuang (*) involves an intricate balance between the pro-
Oral and Maxillofacial Surgery Resident, St. Joseph’s thrombotic activity of platelets, enzymes, and
University Medical Center, Paterson, NJ, USA
coagulation factors and the antithrombotic activity
R. P. Szumita of the fibrinolytic system and coagulation inhibi-
Department of Dentistry/Oral and Maxillofacial
Surgery, St. Joseph’s University Medical Center, tors. A critical component of this balance is the
Paterson, NJ, USA very tissues in which the blood circulates—blood
Private Practice, Little Falls, NJ, USA vessels, endothelium, which lines the vasculature,
e-mail: Szumita@[Link] and subendothelial structures. When uninjured

© Springer International Publishing AG, part of Springer Nature 2018 3

R. P. Szumita, P. M. Szumita (eds.), Hemostasis in Dentistry, [Link]
4 T. Kuang and R. P. Szumita

and in a non-pathologic state, the endothelium Wound healing is described in three phases:
allows blood to remain in a fluid state, preventing inflammatory, proliferative, and maturation. The
pathologic intravascular thrombosis. On the con- inflammatory phase begins immediately follow-
trary, with vessel injury, the endothelium and sub- ing hemostasis and is characterized by local
endothelial tissues are responsible for initiating blood vessel dilation [11, 12]. The time from ini-
the explosion of pro-hemostatic responses culmi- tial vessel constriction to physiologic vasodila-
nating in clotting and cessation of bleeding. tion varies from seconds to several minutes or
Physiologic hemostasis is often described as longer [11, 12]. The time to vasodilation is
occurring in three phases: vascular (local tissues), delayed after dental procedures when local anes-
platelet, and coagulation. Therefore, understand- thetics with vasoconstrictors are used. This is
ing hemostasis begins with understanding the clinically significant in the dental patient, since
basic physiology of the local tissues—blood ves- delayed postoperative bleeding is seen clinically.
sels, endothelium, and subendothelium. It has been shown delayed bleeding can be seen
approximately 6 h after a dental procedure [8]. In
the absence of pathology, this “rebound” bleed-
1.1 Blood Vessels ing is usually minimal and controlled with local
pressure (i.e., gauze pressure to the site).
The initial vascular response to injury is to mini-
mize blood loss followed by initiating the first phase
of wound healing—inflammation [1]. When a 1.2 Endothelium
blood vessel is injured, vasoconstriction of the ves-
sel occurs immediately via neurogenic reflex mech- Endothelium lines the vasculature system, is in per-
anisms from pain and other afferent receptors in the petual contact with flowing blood, and provides the
injured tissue. Vasoconstriction is further supported only barrier between blood and all other tissues.
by a number of endothelial cell and platelet-derived The endothelium is composed of approximately
mediators released at the site of injury and interact- 1–6 × 1013 endothelial cells comprising a surface
ing with the vessel wall smooth muscle. area of between 4000 and 7000 square meters [3,
Vasoconstrictor endothelial mediators released 4]. Aside from serving as a barrier, endothelial cells
include thromboxane A2, endothelin, and endoper- possess multiple metabolic and synthetic functions
oxides (PGH2) [2–5]. Platelet vasoconstrictor medi- exerting their effects on vessel smooth muscle and
ators include thromboxane A2, serotonin (5-HT), components in circulating blood [4]. Endothelial
and ADP [6, 7]. Blood vessel constriction initially cell function, then, is essential in maintaining the
diverts blood flow to the injured site limiting the balance between blood circulating in the fluid state
amount of blood loss and increasing the ability of and initiating the rapid process of clotting when a
attachment of platelets to the injured vessel walls. vessel is injured. Endothelial functions promoting
In dental procedures, epinephrine in local and inhibiting thrombosis are reviewed.
anesthetics has been shown to help in local hemo-
stasis. The smaller blood vessels of the mucous
membranes in the oral cavity primarily contain 1.3 Endothelial Inhibition
α-receptors. Epinephrine is an α-agonist and of Thrombosis
causes vasoconstriction of these local vessels [8].
Increased hemostasis has been demonstrated Intact endothelium functions to maintain blood
with the use of vasoconstrictors present in local flow and reduce the propensity for clotting.
anesthetics [8–10]. Several characteristics are present which help
As part of the normal physiologic process, prevent intravascular clotting in intact endothe-
vessel dilation occurs following initial vasocon- lium and help to control and contain a developing
striction as the initial response to wound healing. thrombus in an injured vessel. The key elements
1 Local Tissues in Hemostasis and Platelet Review 5

supporting antithrombosis are smooth surface; thrombogenic components from endothelial

mucopolysaccharide layer; membrane-bound cells and the subendothelium. One of the criti-
thrombomodulin and antithrombin; and synthesis cal prothrombotic elements exposed from the
and secretion of tissue plasminogen activator endothelium after vessel injury is von
(tPA), prostacyclin, and nitric oxide (NO). Willebrand factor (vWF). The endothelium
The endothelium is smooth in the non-patho- synthesizes two forms of vWF. The first are
logic state. The smoothness helps prevent activa- vWF dimers which are secreted into the plasma
tion of platelets and the initiation of the intrinsic and subendothelium. The second form is stored
coagulation pathway [5]. A “blanket” layer of as multimers in the Weibel-Palade bodies of the
mucopolysaccharides is adherent to the surface of endothelium. With endothelial injury, the stored
the endothelium and repels platelets and clotting vWF is rapidly mobilized. vWF is an important
factors. The mucopolysaccharide layer also serves adhesive protein aiding in platelet adhesion to
as a binding site for antithrombin (also referred to the injured tissue by binding with collagen and
as antithrombin III). Antithrombin is synthesized with the platelet membrane receptor, GPIb/
in the liver and circulates in plasma. Antithrombin IX/V [4, 14].
is a natural anticoagulant which inactivates throm- The primary prothrombotic components
bin and activated factors IX, X, XI, and XII of the exposed in the subendothelium upon vessel
coagulation sequence [2, 3]. injury include tissue factor, collagen, and von
The endothelium also synthesizes and Willebrand factor (vWF).
expresses thrombomodulin on its membrane. Tissue factor (TF) is factor III in the coagula-
Thrombomodulin serves as an antithrombotic by tion sequence and is also known as thrombo-
binding thrombin (factor IIa). Binding of thrombin plastin. TF initiates the coagulation process
serves two functions. Thrombin is powerfully pro- through the extrinsic pathway. The extrinsic
thrombotic via several mechanisms including pathway is activated when exposed TF at the
platelet activation and conversion of fibrinogen site of injury binds activated factor VII (fVIIa).
(factor I) to fibrin. Thrombin is neutralized This binding then initiates coagulation by acti-
when bound to thrombomodulin. In addition, vating factor X of the common pathway [5, 13,
the membrane-bound thrombomodulin-thrombin 15–17].
complex activates a natural anticoagulant, protein Exposed collagen in the subendothelium of
C. Protein C circulates in plasma and, when acti- injured perivascular tissue serves two major
vated, neutralizes activated factors V and VIII (fVa functions. First, collagen is a potent platelet
and fVIIIa) of the coagulation sequence [2, 5, 13]. activator. Second, collagen serves as a binding
(Tissue-type) Tissue plasminogen activator site for platelet adhesion via vWF or as direct
(tPA), prostacyclin, and nitric oxide (NO) are binding to platelet membrane receptor GPVI
synthesized by the endothelium. tPA is an enzyme [13, 18, 19].
which catalyzes the activation of circulating plas-
minogen into plasmin. Plasmin dissolves fibrin
clots [2]. Prostacyclin and NO both inhibit plate- 1.5 Local Tissues Upon
let aggregation and are vasodilatory [4]. Vessel Injury

See Fig. 1.1.

1.4 Endothelial Promotion In summary, the impact injured vascular and
of Thrombosis perivascular (local) tissues have on the process of
bleeding cessation are immediate vasoconstric-
Upon injury of the endothelium and exposure tion decreasing blood flow; platelet activation;
of subendothelium, an explosive prothrombotic providing substrate for platelet adhesion; and ini-
response is initiated. Injury exposes highly tiation of coagulation.
6 T. Kuang and R. P. Szumita

Collagen

Tissue factor (FIII)

TF

von Willebrand factor (vWF)

TF TF
TF
Endothelium

Subepithelium

Fig. 1.1 Exposed bioactive compounds upon damage to endothelium/subepithelium

and not simply a “pass-through” phase on the

Contribution of Local Tissues to Bleeding way to clot generation. The platelet’s central role
Cessation/Thrombus Formation in hemostasis is reviewed.

1. Vasoconstriction with decreased blood Local tissues Coagulation factors

flow to leaking vessel.
2. Platelet activation.
3. Exposure of substrates to allow platelet
adhesion. Platelets
4. Initiation of coagulation.

1.6 Platelet Review Thrombus

Knowledge of platelet physiology is essential for

understanding hemostasis, antiplatelet medica-
tions, and management of patients with bleeding 1.7 Platelet Anatomy
disorders. After vessel wall injury and the expo-
sure of subepithelial elements (discussed above), Platelets are derived from megakaryocytes in
platelets provide the critical platform which bone marrow. They are disc-shaped, anucleate
allows a thrombus to form. Platelets should be cells approximately 2–3 μm in diameter [20]. By
considered the “center” of thrombus formation comparison, red blood cells are approximately
1 Local Tissues in Hemostasis and Platelet Review 7

7 μm, lymphocytes are 6–10 μm, monocytes are tein (GP) designation. The receptors critical to
12–20 μm, and granulocytes are 8–14 μm in platelet function include GPIa/IIa, GPIIb/IIIa,
diameter [21]. GPVI, and GPIb/IX/V (shortened to GPIb).
In the adult, there are approximately one tril- Along with their roles in cellular adhesion, the
lion platelets in circulation—two thirds in the platelet membrane glycoprotein receptors are
general circulation and one third reversibly also involved with intracellular signaling,
sequestered in the spleen. Their average life important in regulating and coordinating the
span is 8–10 days [20]. The primary sites for complex and numerous reactions required for
platelet removal appear to be the spleen, liver, proper platelet function [25, 26]. These func-
and bone marrow [22]. Normal platelet counts tions are discussed below.
are 150,000–400,000 per microliter (μl). To The platelet cytoplasm contains elements to
sustain a steady state of platelets, approxi- form a cytoskeleton, organelles, and intracellular
mately 100 billion new platelets are produced messaging systems. Platelet form is maintained
daily [20]. via a cytoskeleton primarily via spectrin micro-
Platelets are designed to circulate within intact tubules and actin filaments. Organelles in the
vasculature and never interact with the endothe- platelet cytoplasm, including lysosomes and per-
lial surface [19, 23]. However, with disruption of oxisomes, contain a number of degradative
a vessel wall, platelets rapidly respond through a enzymes used against material ingested via
complex of interactions with exposed subendo- phagocytosis. Intracellular messaging is aided
thelial structures to initiate the adhesion of plate- by canalicular and tubular systems within the
lets to the site of injury and clumping together cytoplasm [20].
(aggregation). A large number of biologically active mol-
Structural elements integral in the function ecules are stored in secretory granules within
of platelets are membrane, cytoplasm, and the platelet—α-granules and dense granules.
secretory granules. The platelet membrane is a The α-granules are more abundant. Their con-
phospholipid bilayer. Glycoproteins, choles- tents are involved in hemostasis, immunity,
terol, and glycolipids are embedded within the inflammation, and wound healing [27]. Pro-
platelet membrane and are exposed on the hemostatic substances contained in the
membrane’s external surface [20]. These α-granules are von Willebrand factor (vWF);
exposed membrane molecules, especially the factors I (fibrinogen), V, XI, and XIII; protein
glycoprotein receptors, serve as highly specific S; and platelet activator inhibitor (PAI-1).
surface receptors involved in platelet activa- Dense granules contain serotonin (5-HT), ADP,
tion, adhesion, aggregation, and intracellular ATP, and calcium (factor IV). These substances
signaling [20]. The transmembrane glycopro- are secreted in an orchestrated fashion during
tein receptors are designated by the preface GP. critical steps and during the evolution of the
Glycoprotein receptors have complex struc- thrombus [22, 27].
tures and have also been classified, and referred
to, as integrins—cell adhesion receptors
involved in physiologic and pathologic pro- 1.8 The Platelet
cesses [24]. For purposes of this chapter, the
receptors will be referred to by their glycopro- See Fig. 1.2.
8 T. Kuang and R. P. Szumita

Fig. 1.2 Functional The Platelet:

elements of the platelet

Membrane receptor – GpIb/IX/V

Membrane receptor – GpIIb/IIIa

Membrane receptor – Gp Ia/IIa

Phospholipid membrane

Cytoplasm

Dense granules

Alpha granules

1.9 Platelets and Clotting platelets’ role in the physiologic and pathologic
states.
Platelets are central to the formation of a clot. In patient management, it will help the dental
In physiologic hemostasis, platelets interact at professional to understand the concept of physi-
the site of disruption of vessels (surgery or ologic and pathologic thrombi formation. Dental
trauma) in the prevention of bleeding. Platelets treatment of patients being managed with anti-
also play a role in the formation of pathologic platelet medications to reduce the risk of patho-
thrombi, mircothrombi, and emboli that are logic thrombus formation can often be
associated with myocardial infarction, stroke, accomplished with minimal impact on the physi-
pulmonary embolism, and end-organ damage. ologic formation of a wound thrombus (discussed
There are both similarities and differences in further in chapters).
1 Local Tissues in Hemostasis and Platelet Review 9

collagen, tissue factor (factor III), and others.

Rapid interactions occur between these subendo-
Platelet thelial structures and circulating platelets to initi-
ate the hemostatic process [19]. These initial
reactions activate the circulating platelets predis-
posing them to adhere to the damaged endothe-
lium. Platelets then coalesce or aggregate. This
“clump” of platelets is then able to focus and
Physiologic Pathologic direct multiple biochemical reactions at the site
of injury leading to the formation of fibrin.
Research continues to reveal the central roles and
complex nature platelets play in hemostasis.
Recent findings suggest there may actually be
Formation of a Formation of
different platelet populations, with distinct sur-
clot at the site of thrombi, face properties, each group designed to carry out
vessel injury to microthrombi, different roles in coagulation [28].
stop hemorrhage emboli

1.11 Platelet Activation

1.10 Platelets in Physiologic Platelets circulate in a non-activated state. Upon

Hemostasis vessel injury, platelet membrane receptors inter-
act with the damaged endothelium and subendo-
Platelets perform several important functions in thelial substances leading to platelet activation.
physiologic coagulation: control of thrombin A major pathway in platelet activation is colla-
generation, support of fibrin formation, and regu- gen binding to platelet membrane GPVI [17].
lation of fibrin clot retraction [28]. Additionally, Additional activation occurs with the binding of
platelets anchor these functions directly at the vWF to platelet membrane GPIb [19, 23]. Other
site of tissue/vessel injury. substances shown to promote platelet activation
include thrombin, thromboxane A2, 5-HT, epi-
nephrine, and ADP. With activation, several
Platelet Functions in Physiologic structural and physiologic changes occur to the
Hemostasis [28] platelet and include platelet shape change,
expression of pro-inflammatory molecules,
1. Control of thrombin generation. expression of platelet procoagulant activity,
2. Support of fibrin formation. potentiation of aggregation by other prothrom-
3. Regulation of fibrin clot retraction. botic factors (i.e., collagen), and conversion of
4. Anchor the reactions at the site of tissue platelet receptor GpIIb/IIIa into active form [29,
injury/hemorrhage. 30]. Platelet activation “primes” the platelet to
begin its pro-hemostatic and pro-healing
functions.
To accomplish these functions, platelets go
through well-coordinated and regulated pro-
cesses: activation, adhesion, aggregation, and 1.12 Platelet Adhesion
secretion.
Immediately after vessel injury from surgery Once activated, platelets are “primed” to adhere
or trauma, vessel vasoconstriction occurs and to the injured site—a critical step in formation of
subendothelial substances are exposed: vWF, an effective thrombus. Platelet adhesion relies
10 T. Kuang and R. P. Szumita

primarily on exposed collagen at the site of arteries) in the injured vessel. GPVI also likely
injury, vWF, and glycoprotein receptors in the binds directly to collagen but may have a greater
platelet membrane. [It is important to note here role as an activator of GPIa/IIa via intracellular
that another substance is exposed after endothe- signaling [19, 34].
lial damage—tissue factor (factor III). As will be Other proteins in the subendothelial matrix
discussed shortly, tissue factor is responsible for have also been shown to play a role in platelet
initiating the process of thrombin and fibrin function: fibronectin, thrombospondin, lam-
formation.] inin, and vitronectin. Fibronectin and thrombo-
The initial critical step in adhesion involves spondin are both stored in α-granules in
von Willebrand factor (vWF) and the platelet gly- platelets. Fibronectin binds to platelet mem-
coprotein receptor Ib/V/IX (GPIb). von brane glycoprotein (GPIIb/IIIa) which is
Willebrand factor (vWF) is a large glycoprotein involved in ­ platelet aggregation (discussed
found in several locations: in the circulation in an below). Thrombospondin release from the
inactive form, in the subendothelial matrix of platelets with subsequent binding to the platelet
blood vessels, within Weibel-Palade bodies of membrane interacts with fibrinogen, fibrin, and
endothelial cells, and in α-granules of platelets collagen. These interactions appear to help
[25, 31]. Platelet receptor GPIb/IX/V is a com- overcome local antithrombotic activity by pro-
plex of glycoproteins on the platelet membrane viding positive feedback, enhancing platelet
where the major binding site is on the glycopro- adhesion and aggregation [19].
tein (GP) Ib subunit. In hemostasis, GPIb binds Laminin is a large glycoprotein in the suben-
vWF [14, 32]. GPIb also binds a leukocyte recep- dothelial matrix. Laminin acts like collagen by
tor (Mac-1) which plays a role in vessel wall binding to platelet membrane receptor GPVI
inflammation in atherosclerosis, thrombosis, and leading to platelet activation. Laminin also inter-
restenosis [33]. acts with the binding of vWF and platelet GPIb
Upon endothelial damage, collagen becomes further enhancing platelet adhesion [19, 35].
exposed and binds vWF. Binding of vWF causes Vitronectin is also found in the subendothelial
a conformational change in the molecule and matrix and, like fibronectin, binds to platelet
exposes the binding site for the platelet mem- membrane receptor GPIIb/IIIa enhancing platelet
brane GPIb. vWF then acts as the link anchoring aggregation [19].
collagen at the site of vessel injury and the
platelet via GPIb receptor [19, 32]. This interac-
tion appears to be critical especially in high 1.13 Platelet Aggregation
flow, high shear stresses in injured vessels—
microvascular and stenotic arteries [34]. This Aggregation of platelets to each other is the
initial bonding decelerates platelets and holds next step in the evolution of a thrombus. This
them in close contact with the exposed subendo- “clumping” together of platelets occurs pri-
thelial matrix where additional interaction with marily between platelet membrane glycopro-
platelet receptors leads to further activation and tein receptors (GPIIb/IIIa) and fibrinogen.
adhesion [17, 23]. Fibrinogen is the intermediary between GPIIb/
Additional anchoring of platelets to the site of IIIa receptors on adjacent platelets. GPIIb/IIIa
vessel injury is provided by direct collagen bind- can also bind vWF assisting in aggregation
ing to platelet membrane receptor glycoproteins: (Note: GPIIb/IIIa is also referred to in the lit-
GPIa/IIa and GPVI. GPIa/IIa binds directly to the erature as αIIbβ3 integrin.) [26]. Platelet aggre-
collagen types I and IV found in the subendothe- gation results in concentrating a greater volume
lial matrix. This binding is thought to be limited of platelets at the site of injury, providing
to low shear stress conditions (veins and larger membrane surfaces for the anchoring of the
1 Local Tissues in Hemostasis and Platelet Review 11

coagulation reactions terminating in the con-

version of fibrinogen (factor I) to fibrin at the Pathologic
thrombi
site of injury.

1.14 Platelet Quality: Secretion

Arterial Venous

Among its attributes, the platelet is a biochemical

manufacturing and storage “warehouse.”
Dentistry has extensively studied and employed
Thrombus Thrombus
platelet concentrates in clinical practice for its anchored by anchored by
positive effects on wound and bone healing [36– platelets fibrin
39]. Platelets store a multitude of substances that
are important in hemostasis as well as in healing.
These bioactive substances are contained in In the arterial system, mechanisms proposed to
α-granules, dense granules, and the cytoplasm. explain pathologic thrombi formation include rup-
The stored molecules involved in hemostasis are ture of atherosclerotic plaques, deformation of
as follows. α-Granules contain vWF; factors I vWF in high shear stress arterial vessels, and sys-
(fibrinogen), V, and XI; protein S; PAI-1; and temic inflammatory states. When atherosclerotic
HMWK. Dense granules contain serotonin, ADP, lesions rupture, vWF and collagen can become
ATP, and calcium. The cytoplasm contains factor exposed initiating platelet activation, adhesion, and
XIII. These substances are secreted during the coagulation. In partially occluded arteries, high
evolution of the thrombus [22]. sheer stress of the blood flow can alter (“unfold”)
vWF allowing it to bind to platelet receptor GPIb/
IX/V and initiate clotting. Systemic inflammatory
1.15 Platelets in Pathologic states are associated with many d­ iseases including
Hemostasis (Thrombotic cardiovascular disease. Inflammatory states are
Disease) known to activate platelets and promote endothelial
cell dysfunction by making them more adhesive to
The formation of pathologic thrombi in both the circulating platelets.
arterial (myocardial infarction and stroke) and Venous thromboembolism is less well under-
venous (deep vein thrombosis potentially leading stood but appears to be related to inflammation
to pulmonary emboli) vasculature is well docu- and stasis [40].
mented. Even though pathologic clotting (within
vessels with intact endothelium) shares similari-
ties to physiologic clotting, many mechanisms for References
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clotting even differ between the arterial and surgery: the biological basis of modern surgical prac-
tice. 19th ed. Philadelphia, PA: Elsevier Saunders;
venous systems. Arterial pathologic thrombi 2012.
appear to be anchored to vessel walls by platelet 2. Shuman MA. Endothelial cell structure and function.
interactions. In venous thromboembolism, fibrin In: Hoffman R, Benz Jr EZ, Edward J, Shattil SJ, Furie
appears to be the main mediator anchoring the B, Cohen HJ, Silberstein LE, editors. Hematology:
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