hemostasis :Mechanism and causes of its dysregulation.pdf

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 andactivation 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 hemostatic plug and activates clot lysis.

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

3. Contents
•Introduction
•Models of Hemostasis
•Mechanisms by which inflammation
induces disturbance of the
hemostatic system
•Platelet Activation by Cancer Cells
•Pathological hemostasis
•Stress and Hemostasis
•Influence of antidepressants on
hemostasis
•Hemostasis and aging

4. 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.

5. 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
Liischerand Weber (1993), Marcus and
Sailer (1993), Caen and Rosa (1993), and
Hawiger(1995)

7. 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.
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.

8. 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/VIIacomplex is anchored to a
TF-bearing cell, where the TF has a
cytoplasmic domain, a transmembrane
domain, and an intracytoplasmic
domain.

10. 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 can
activate platelets, factor VIII, factor V, and factor XI
and separating factor

11. 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 IXaformed 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.

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

13. 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

18. 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 vWFin humans and some
animal species, and fibronectin;
participating in surface adhesion andactivationprocessess(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 hernostaticplug and activates clot lysis.

19. 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

20. 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

22. 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
theplatelet membrane, are
outlined.
(Davenport DJ, Breitschwerdt
EB, CarakostasMC: Platelet
disorders in the dog and cat.

24. 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

25. 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 VIIIaescaping from the
endothelial cell surface (fig. 3).

26. •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.

30. 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 tenasecomplex
(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.

36. Fibrinolysis

37. Fibrinolysis involves a series of events critical to the
removal of the hemostatic plug during 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).

39. Models of
Hemostasis

40. 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.

41. 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.

45. Inflammation
and
haemostasis

46. 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

47. Mechanisms by which inflammation
induces disturbance of the hemostatic
system

48. 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).

58. Hemostasis and
Malignancy

59. 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).

61. 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).

62. 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).

63. Histological Evidence That
Hemostasis Plays a Role in
Tumor Biology

64. 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 FpAlevels commonly
observed in patients with
malignant disease.

65. The activation of the clotting process in
cancer is amultifactorial 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.

66. Platelet Activation by
Cancer Cells

67. 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.

68. 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.

69. Pathological
hemostasis

70. •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.

74. Stress and
Hemostasis

75. 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

76. 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.

77. “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”)..

78. 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.

80. 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 factors modulate and
acquired prothrombotic conditions
enhance the prothrombotic stress
response, which may 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

83. Influence of antidepressants
on hemostasis

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

85. The observation that depression is an independent risk factor for
cardiovascular mortality 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).

86. 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.

89. Hemostasis and
aging

90. 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.

91. 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].

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