hemostasis.pptx

Hemostasis
By
Romissaa Aly
Assistant lecturer of Oral
Medicine, Periodontology,
Diagnosis and Dental Radiology
(Al-Azhar University)

When a blood vessel is injured or severed, a brief
local reflex vasoconstriction occurs that reduces blood
flow at the site.
Vascular contraction is maintained by the release
of vasoactive compounds from adjacent platelets and
surrounding tissues.
Simultaneously, platelets in the vicinity adhere to
exposed subendothelial collagen fibers.

This interaction with collagen causes a "release
reaction" whereby platelet constituents,
such as adenosine diphosphate (ADP), serotonin,
epinephrine, and histamine, are released into the
surrounding medium.

The role of platelets in sustaining
hemostasis has been reviewed by Liischer
and Weber (1993), Marcus and Sailer
(1993), Caen and Rosa (1993),
and Hawiger (1995)

Intact endothelium does not promote platelet or
leukocyte adherence nor does it activate coagulation

Both active and passive mechanisms apparently play a
role in maintaining thromboresistance, and
endothelial cells actively contribute to this
thromboresistance by regulating a complex balance
between the procoagulant and anticoagulant properties
of the vasculature
(Breider, 1993; Griendling and Alexander, 1996).

 AS early as 1964, it was proposed that coagulation
reactions leading to hemostasis occurred in
sequential steps in which a zymogen clotting
factor, when activated, was capable of activating
subsequent clotting factors in a waterfall or cascade
mechanism.

Although not shown in figure 1, it is now known that
factor VIII circulates in complex with von
Willebrand factor, the latter acting as a carrier
molecule that serves to transport factor VIII from
circulation to the platelet surface
by virtue of the binding of von Willebrand factor.
von Willebrand factor also plays a role in the adhesion
of platelets to components of the vessel wall.

Recently, the work of several investigators has
indicated that the initiating event leading to the
hemostatic plug is the exposure of TF and the
formation of a TF/VIIa complex.
This TF/VIIa complex is anchored to a TF-bearing
cell, where the TF has a cytoplasmic domain, a
transmembrane domain, and an intracytoplasmic
domain.

Fig. 1. Intrinsic system represents the clotting factors in the
circulating blood. Extrinsic system represents tissue factor (TF)
in complex with factor VII. Activation of factor XII was thought
to be due to exposure of surface collagen and required cofactors
prekallikrein (PK) and high-molecular-weight kininogen (HK).
a activated; roman numerals clotting factors.

Role of the Tissue Factor–bearing Cell
Cells expressing TF are found in extravascular cells
surrounding blood vessels as well as other tissues.
TF is also present in circulating leukocytes, but it is
usually encrypted, i.e., not active except under
certain circumstances.

This small amount of thrombin serves as a
priming mechanism for subsequent hemostatic events
as shown in figure 2 (top panel).
 As can be seen, this small amount of thrombin is
capable of activating platelets, factor VIII, factor V,
and factor XI and separating factor

It is assumed that the TF cell is extravascular,
though there is evidence suggesting that encrypted
blood TF can be “decrypted” and discharged
from leukocytes as microparticles that associate with
platelets.

The factor IXa formed by the TF-bearing cell does
not remain in the vicinity of the cell but rather
occupies a binding site, probably a specific binding
protein, on the activated platelet surface adjacent to its
cofactor, factor VIIIa.
Subsequent events leading to thrombin generation
take place on the surface of activated platelets.

Role of the Activated Platelet
As shown in figure 2 (bottom panel), activated platelets
serve to bind the cofactors VIIIa and Va first and
subsequently their respective enzymes, factors IXa and
Xa.

Factor IXa on the activated platelet surface and in
the presence of its cofactor VIIIa then recruits more
factor X from solution and activates factor X to Xa.
Factor Xa then occupies a binding protein on the platelet
surface adjacent to its cofactor, factor Va, to form the
prothrombinase complex.

This prothrombinase complex is capable of
converting large amounts of prothrombin to
thrombin in amounts sufficient to clot fibrinogen
(fig. 2, bottom panel).

In addition, thrombin generation can be boosted
by factor XIa, which can convert more IX to IXa,
ultimately leading to an increase in thrombin
generation.
This concept explains why factor XI deficiency is
always mild. Even if there were no factor XI,
individuals would still have tenase and prothrombinase
complexes

Platelets have many functions, including
phagocytosis of viruses, latex, immune complexes
and iron; maintenance of vascular integrity by
filling gaps that form in the endothelium and by
directly supporting endothelial cells; synthesis and
release of vWF in humans and some animal species,
and fibronectin;

participating in surface adhesion and
activation processess (Caen and Rosa, 1995;
Clemetson, 1995; Nurden, 1995); production and
release of potent smooth muscle and
endothelial cell proliferating factor( s); and
retraction of clots, a process that stabilizes the initial
hernostatic plug and activates clot lysis.

Additionally, platelets play an important regulatory
role via prostaglandin pathways in promoting
hemostasis and thrombosis and in maintaining the
thromboresistance of intact endothelium (Herman et
al., 1991).
This involves metabolism of arachidonic acid released
from platelet phospholipids

. A potent but unstable platelet-aggregating agent
and vasoconstrictor, thromboxane A2 (TxA2), is
produced from cyclic endoperoxides by the action of
cyclooxygenase on arachidonic acid (Johnson et al.,
1991

 The potent aggregating effect of TxA2 on
platelets is inhibited by the production of
prostaglandins E1 and D2 (PGE1 and PGD2) from
linolenic and linoleic adds.
 Thus, platelet phospholipidand lipid metabolism
plays a crucial role in the stimulation and inhibition of
platelet reactivity..

Aspirin is an effective inhibitor of the platelet release
reaction because it acetylates cyclooxgenase and
inhibits TxA2 production (Grauer et al., 1992).
A key component of the platelet prostaglandin
regulatory mechanism of hemostasis and
thrombosis is the production of prostacyclin (PGI2) by
endothelium and other vascular tissues

Schematic representation of the role
of prostaglandins in regulation of
platelet
cAMP level and activity. The
interdependent roles of prostacyclin,
derived from the vascular
endothelium, and thromboxane,
derived the the platelet membrane,
are outlined. (Davenport
DJ, Breitschwerdt EB, Carakostas MC:
Platelet disorders in the dog and cat.

FIGURE 10.2
Instrinsic and
extrinsic systems
of blood
Coagulation.
HMWK, high
molecular
weight kininogen.

Role of Endothelial Cells
With the injury to the vessel wall, there is exposure
of TF in the extravascular space leading to the events
noted in figure 2.
Thus, an injury in the vessel wall results in the
formation of a hemostatic plug consisting of a
mass
of activated platelets interspersed with fibrin..

Thrombin generation would then need to be
limited precisely to the site of the vessel wall injury.
This is accomplished by control mechanisms as
indicated in figure 3.
The excess thrombin that would gain access to the
circulation would be inhibited by antithrombin

It would also be inhibited on adjacent normal
endothelium because the thrombin escaping
from the initial hemostatic plug would occupy
thrombomodulin on the endothelial cell to form a
thrombin/thrombomodulin complex.

 The thrombin/thrombomodulin complex
would activate protein C, which, in the
presence of its cofactor (protein S), would
be capable of inactivating both Va and VIIIa
escaping from the endothelial cell surface (fig.
3).

Fig. 3. APC activated protein C; AT antithrombin; GAG
glycosaminoglycans with antithrombin inhibit excess
thrombin; PC protein C; S protein S, the cofactor of protein C; T
thrombin; TF tissue factor; TM thrombomodulin. Va and VIIIa
with slashes indicate Va and VIIIa inactivated by activated
protein C. Activated platelets and fibrin form a hemostatic plug.

FIGURE 4. Stages of platelet activation and thrombus
formation. Platelets adhere to a von Willebrand factor
(VWF)/collagen matrix, get activated, secrete granular
contents, aggregate via integrins, produce thrombin
after developing a procoagulant surface, and form a
contracted thrombus with fibrin. Heat map with color
codes from green (low Ca2 signal) to red (high Ca2 signal).
Interactions of platelets with coagulation factor
are indicated, as described. Note that procoagulant platelets
provide a phosphatidylserine (PS)-exposing
surface for the tenase complex (activated FVIII and FIX) and
the prothrombinase complex (activated FV and FX).
Formed thrombin provides positive-feedback reactions to
activate platelets via GPCR, to activate coagulation
factors, and to convert fibrinogen into fibrin.

Fibrinolysis involves a series of events critical to the
removal of the hemostatic plug in the course of vessel
healing and repair
(Fareed et al., 1995; Lijnen and Collen, 1995;
Verstraete, 1995).
Anoutline is shown in Fig. 10.3, and a detailed
description is given by Verstraete (1995).

After direct or indirect activation of the
fibrinolytic system, plasminogen is converted to
plasmin. Plasmin actively digests fibrin, fibrinogen, and
factors V and VIII.
 This mechanism is analogous to that of coagulation in
that an active enzyme, plasmin, is formed by activation
of its precursor, plasminogen (McKeever et al., 1990).

Hemostasis is an essential protective mechanism
that depends on a delicate balance of procoagulant
and anticoagulant processes.
The waterfall/cascade models of coagulation
are useful for understanding several
essential steps of coagulation in vitro.

 These have resulted in the creation of the
plasma-based tests used commonly and the
ability to identify deficiencies in the extrinsic,
intrinsic, and common pathways of coagulation.

The model was also essential in elucidating
the role of several of the inhibitors of
coagulation
and is currently used to demonstrate coagulation as
it occurs in plasma in a static environment that is
devoid of endothelial interactions.

The intrinsic pathway originally described by these
models does not appear to be essential for in vivo
hemostasis but may play a role in pathologic
thrombosis.
The waterfall/cascade models’ lack of cellular
elements sets the stage for the cell-based model of
coagulation.

In this bidirectional relationship,
inflammation leads to activation of the haemostatic
system that in turn also considerably influences
inflammatory activity (1,2).

. Inflammation shifts the haemostatic activity
towards procoagulant state by the ability of
proinflammatory mediators to activate coagulation
system and to
inhibit anticoagulant and fibrinolytic activities.

In turn, uncontrolled activation of the haemostatic
system can also amplify the initial Inflammatory
response thus causing additional organ
injury.

Such, the haemostatic system acts in
concert with the inflammatory cascade creating
an inflammation-haemostasis cycle in which
each activated process promotes the other and
the two systems function in a positive feedback
loop

Mechanisms by which
inflammation
induces disturbance of
the haemostatic
system

The main mediators of inflammation-induced
activation of the haemostatic system are proinfl
ammatory cytokines tumour necrosis factor-alpha
(TNF-α), interleukin 1 (IL-1) and interleukin 6 (IL-6) .

Inflammatory mediators trigger disturbance of the
haemostatic system in a number of mechanisms
including endothelial cell dysfunction,
 increased platelet activation, tissue factor
(TF) mediated activation of the plasma
coagulation cascade, impaired function of
physiologic anticoagulant pathways and suppressed
fibrinolytic activity (Figure 1).

There is considerable evidence that the
hemostatic system is involved in the growth and
spread of malignant disease.
 There is an increased incidence of
thromboembolic disease in patients with
cancers and hemostatic abnormalities are
extremely common in such patients.

There are several important phases in the
formation of blood-borne metastases:
neovascularization (angiogenesis), shedding of
cells from the primary tumor, invasion of the
blood supply, movement of tumor cells to
other sites, adherence to the vessel wall,
extravasation,
and growth at the metastatic site (Fig. 1).

 Not all tumor types are equally associated with
thrombotic events; patients with tumors of the lung,
pancreas, and gastrointestinal tract tend to be more
hypercoagulable than those with breast or kidney
cancer.3
Surgery is a front-line treatment for many cancers, but
such patients have an increased chance of developing
postoperative deep vein thrombosis (DVT).

Hemorrhage may also occur in patients with
malignant disease, but it is less common than
thrombosis.
Local bleeding may result from tumor
infarction or invasion of blood vessels, while
more generalized hemorrhage results from bone
marrow metastases or acute disseminated
intravascular coagulation (DIC).

Histological Evidence
That Hemostasis
Plays a Role in Tumor
Biology

Fibrin is an early and consistent marker of tumor
cell stroma,99 being deposited within hours of tumor
implantation and remaining throughout the course of
tumor growth.

Fibrin deposits persist throughout the course
of inflammation, as loss of fibrin due to
fibrinolysis is balanced by further fibrin formation

 As macrophage infiltration is also a feature of
tumor pathology, these findings also have
implications in peritumor fibrin formation.
Extravascular fibrin formation may partially
account for the elevated FpA levels commonly
observed in patients with malignant disease.

The activation of the clotting process in cancer is a
multifactorial process.
This includes a variety of nonspecific
mechanisms such as tissue damage and
inflammatory response that result in tissue
factor (TF) expression and coagulation activation.
However, other more specific mechanisms may exist.

Platelet Activation by
Cancer Cells

The requirement for platelets in experimental
models of metastasis was recognized almost 30
years ago.
Platelets are an integral part of themicrothrombus
thought to be involved in the arrest and lodgment
of circulating malignant cells

They may be activated by malignant cells, and tumor
cell-induced platelet aggregation
occurs both in vivo and in vitro.
The aggregating activity of tumor cells may be
associated with cell membrane fragmentsor
plasma
membrane vesicles shed by the abnormal cells.

 The binding of tumor cell vesicles to platelets
initially depends on complement activation, which
leads to platelet aggregation, possibly because of
thrombin formation by the tumor-platelet complex.

An increased density of sialic acid residues on
the tumor cell surface may enhance
platelet aggregation,reduce attachment to
basement membrane proteins, and
predispose the tumor cells to increased mobility
and decreased growth control.

Disorders of primary hemostasis
Both constitutive and acquired defects of
primary hemostasis preferentially induce sc or
mucosal bleeding, appearing spontaneously or
after minimal trauma.
Platelet and vWF abnormalities are the most
frequent.

As a prerequisite for the notion that stress-
associated hypercoagulability contributes to
thrombotic events,
abundant epidemiological and experimental
data exist supporting the role of enhanced
coagulation, impaired fibrinolysis, and
hyperactive platelets in the development of
atherogenesis, atherothrombosis, and
acute coronary syndromes (ACSs).2

Also, against a background risk from acquired
prothrombotic conditions (e.g., varicosis,
immobility) and inherited thrombophilia,
even
“trivial” triggers such as stress, might bring
forward a prothrombotic state that results in
onset of venous thromboembolism
(VTE).

 After introducing the evolutionary meaning
versus
potential harm for the vasculature of a
prothrombotic stress response, we present
epidemiological and observational
data on the role of stress in atherothrombotic
diseases and VTE.

“Stress” is an ambiguous term embedding different
processes, namely, a stimulus (i.e., the “stressor” in
the form of environmental challenges), perceptual
processing of this input (i.e., perceived
“distress” with the accompanying negative
effects),
and behavioral and physiological output (i.e., the
“stress response”)..

This cascade of events helps explain why not
only demanding life circumstances (e.g.,
providing care to a spouse with dementia,
working overtime), but also perceived distress
(e.g., depressive symptoms) arising from such life
circumstances have emerged as risk factors of
CVD.7.

Fig. 1 Processes in the relationship between stress, hemostasis,
and thrombosis. Depending on cortical information processing
and appraised
coping resources, environmental challenges initiate autonomic-
and neuroendocrine-driven changes in the hemostatic system.
Several
demographic and health-related factorsmodulate and acquired
prothrombotic conditions enhance the prothrombotic stress
response, whichmay
become pathological if excessive or chronic, thereby increasing
thrombosis risk. Coag, coagulation activation; FL, fibrinolysis
activation; HPA,
hypothalamic–pituitary–adrenal axis; SNS, sympathetic nervous
system

Notes: Qualitative changes
(", increased level; #,
decreased level; —, no
change; ?, unclear). While
there is coagulation and
platelet activation in
both acute and chronic
stress conditions, fibrinolysis
is activated with
acute stress but attenuated
with chronic stress

Influence of
antidepressants on
hemostasis

Antidepressants, particularly selective serotonin
reuptake inhibitors (SSRIs), are widely used for the
treatment of depression and anxious disorders.

The observation that depression is an independent
risk factor for cardiovascular mortality and
morbidity in patients with ischemic heart disease,
the assessment of the central role of serotonin
in pathophysiological mechanisms of
depression, and reports of cases of abnormal
bleeding associated with antidepressant therapy have
led to investigations of the influence of
antidepressants on hemostasis markers.

Drugs with the highest degree of serotonin
reuptake inhibition—fluoxetine, paroxetine,
and sertraline— are more frequently associated
with abnormal bleeding and modifications of
hemostasis markers.
The most frequent hemostatic abnormalities are
decreased platelet aggregability and activity, and
prolongation of bleeding time.

Patients with a history of coagulation disorders,
especially suspected or documented
thrombocytopenia or platelet disorder,
should be monitored in case of prescription of any
serotonin reuptake inhibitor (SRI).

Platelet dysfunction, coagulation disorder, and von
Willebrand disease should be sought in any case of
abnormal bleeding occurring during treatment
with an SRI.
Also, a non-SSRI antidepressant should be
favored over an SSRI or an SRI in such a context.

Many changes in the vasculature, hemostasis and
endothelium, including alterations of platelets,
coagulation and fibrinolytic factors, occur
during aging.

While the increasing hypercoagulability
observed with aging may account for the higher
incidence of thrombotic cardiovascular disorders
in the elderly, the lack of genetic protective factors
against thrombosis in healthy centenarians suggests
that little is yet known about the age-associated
changes of hemostasis.

The mechanism has not yet been elucidated,
but fibrinogen could contribute to enhanced
thrombosis by being a direct substrate for the clot,
by enhancing bridging of platelets or by increasing
the viscosity of blood [21].

references
1.Roberts HR, Monroe DM, Escobar MA, Weiskopf RB. Current
concepts of hemostasis: implications for therapy. The Journal of the
American Society of Anesthesiologists. 2004 Mar 1;100(3):722-30.
2.Dodds WJ. Hemostasis. InClinical biochemistry of domestic
animals 1997 Jan 1 (pp. 241-283). Academic Press.
3. Franchini M. Hemostasis and aging. Critical reviews in
oncology/hematology. 2006 Nov 1;60(2):144-51.
4. Francis JL, Biggerstaff J, Amirkhosravi A. Hemostasis and
malignancy. InSeminars in thrombosis and hemostasis 1998 Apr
(Vol. 24, No. 02, pp. 93-109). Copyright© 1998 by Thieme Medical
Publishers, Inc..
5. Lasne D, Jude B, Susen S. From normal to pathological
hemostasis. Canadian journal of anaesthesia= Journal canadien
d'anesthesie. 2006 Jun 1;53(6 Suppl):S2-11.
6.Margetic S. Inflammation and hemostasis. Biochemia medica.
2012 Feb 15;22(1):49-62.

7. McMichael M. New models of hemostasis. Topics in
companion animal medicine. 2012 May 1;27(2):40-5.
8. Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New
fundamentals in hemostasis. Physiological reviews. 2013
Jan;93(1):327-58.
9. Austin AW, Wissmann T, von Kanel R. Stress and hemostasis: an
update. InSeminars in thrombosis and hemostasis 2013 Nov (Vol.
39, No. 08, pp. 902-912). Thieme Medical Publishers.
10. Troy GC. An overview of hemostasis. Veterinary Clinics of North
America: Small Animal Practice. 1988 Jan 1;18(1):5-20.
11,Halperin D, Reber G. Influence of antidepressants on hemostasis.
Dialogues in clinical neuroscience. 2022 Apr 1.

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