Hemostasis
Mechanisms of Hemostasis
Hypercoagulability States
Bleeding Disorders
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hemostasis refers to the stoppage of
blood flow
The normal process of hemostasis is
regulated by a complex array of
activators and inhibitors that maintain
blood fluidity and prevent blood from
leaving the vascular compartment.
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Hemostasis is normal when it seals a blood
vessel to prevent blood loss and hemorrhage.
It is abnormal when
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it causes inappropriate blood clotting
or when clotting is insufficient to stop the flow of
blood from the vascular compartment.
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Disorders of hemostasis fall into two
main categories:
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the inappropriate formation of clots within
the vascular system (i.e., thrombosis) and
the failure of blood to clot in response to
an appropriate stimulus (i.e., bleeding)
MECHANISMS OF HEMOSTASIS
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Hemostasis is divided into five stages:
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vessel spasm,
formation of the platelet plug,
blood coagulation or development of an
insoluble fibrin clot,
clot retraction, and
clot dissolution
Vessel spasm
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Vessel spasm is initiated by endothelial injury and caused by
local and humoral mechanisms.
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A spasm constricts the vessel and reduces blood flow.
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It is a transient event that usually lasts less than 1 minute.
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Thromboxane A2 (TXA2), a prostaglandin released from the
platelets, contributes to the vasoconstriction.
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A second prostaglandin, prostacyclin, released from the vessel
endothelium, produces vasodilation and inhibits platelet
aggregation.
Formation of the Platelet Plug
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The platelet plug, the second line of
defense, is initiated as platelets come in
contact with the vessel wall.
The outside of the platelet membrane is
coated with glycoproteins that
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repulse adherence to the normal vessel
endothelium, while causing
adherence to injured areas of the vessel
wall, particularly the subendothelial layer.
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The platelet membrane also has
glycoprotein receptors that bind
fibrinogen and link platelets together.
Glycoprotein receptor antagonists have
been developed and are selectively
used in the treatment of acute coronary
myocardial infarction
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Platelet plug formation involves adhesion and
aggregation of platelets.
Platelet adhesion also requires a protein
molecule called von Willebrand factor (vWF).
vWF, which is produced by the endothelial
cells of blood vessels, performs two important
functions:
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it aids in platelet adhesion, and it
circulates in the blood as a carrier protein for
coagulation factor VIII.
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Platelets are attracted to a damaged
vessel wall, become activated, and
change from smooth disks to spiny
spheres, exposing receptors on their
surfaces.
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Adhesion to the vessel subendothelial
layer occurs when the platelet receptor
binds to vWF at the injury site, linking
the platelet to exposed collagen fibers
Blood Coagulation
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Blood coagulation is controlled by many substances that
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promote clotting (i.e., procoagulation factors) or
inhibit it (i.e., anticoagulation factors).
The action of one coagulation factor or proenzyme is designed to
activate the next factor in the sequence (i.e., cascade effect).
Abnormalities of the clotting process occur when one or more of the
factors are deficient or when conditions lead to inappropriate activation
of any of the steps.
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The chemical events in the blood
coagulation process involve a number of
essential steps that result in the
conversion of fibrinogen, a circulating
plasma protein, to the fibrin strands
that enmesh platelets, blood cells, and
plasma to form the clot
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The initiation of the clotting process
occurs by way of the intrinsic or the
extrinsic coagulation pathways
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The intrinsic pathway, which is a relatively slow
process, begins in the blood itself.
The extrinsic pathway, which is a much faster
process, begins with tissue or vessel trauma and the
subsequent release of a complex of several factors,
called tissue factor, or tissue thromboplastin.
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The terminal steps in both pathways are the same:
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the activation of factor X,
the conversion of prothrombin to thrombin, and
the conversion of fibrinogen to fibrin.
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The intrinsic system is activated as
blood comes in contact with collagen in
the injured vessel wall and the
extrinsic system when blood is exposed
to tissue extracts.
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With few exceptions, almost all the
blood-clotting factors are synthesized in
the liver.
Vitamin K is required for the synthesis
of prothrombin, factors VII, IX, X, and
protein C.
Calcium (factor IV) is required in all but
the first two steps of the clotting
process.
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Coagulation is regulated by several
natural anticoagulants. Antithrombin III
inactivates coagulation factors and
neutralizes thrombin
Clot Retraction
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After the clot has formed, clot
retraction, which requires large
numbers of platelets, contributes to
hemostasis by squeezing serum from
the clot and joining the edges of the
broken vessel.
Clot Dissolution
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The dissolution of a blood clot begins
shortly after its formation; this allows
blood flow to be re-established and
permanent tissue repair to take place
The process by which a blood clot
dissolves is called fibrinolysis.
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Plasminogen, the proenzyme for the
fibrinolytic process, normally is present
in the blood in its inactive form.
It is converted to its active form,
plasmin, by plasminogen activators
formed in the vascular endothelium,
liver, and kidneys.
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The plasmin formed from plasminogen
digests the fibrin strands of the clot and
certain clotting factors
Circulating plasmin is rapidly inactivated
by α2-plasmin inhibitor
Hints on normal vascular hemostasis
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Normal hemostasis: results from well-regulated
processes that maintain blood in a fluid, clot-free state in
normal vessels while inducing the rapid formation of a
localized hemostatic plug at the site of vascular injury.
Thrombosis:is the pathologic converse to hemostasis it
can be thought of as the formation of a blood clot
(thrombus) in uninjured vessels, or thrombotic occlusion
of a vessel after relatively minor injury.
Both hemostasis and thrombosis are dependent on three
general components:
the vascular wall, platelets, and the coagulation cascade
Hints on normal vascular hemostasis
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Normal hemostasis: results from well-regulated
processes that maintain blood in a fluid, clot-free state in
normal vessels while inducing the rapid formation of a
localized hemostatic plug at the site of vascular injury.
Thrombosis:is the pathologic converse to hemostasis it
can be thought of as the formation of a blood clot
(thrombus) in uninjured vessels, or thrombotic occlusion
of a vessel after relatively minor injury.
Both hemostasis and thrombosis are dependent on three
general components:
the vascular wall, platelets, and the coagulation cascade
Endothelial cells modulate several aspects of normal
hemostasis:
- On the one hand, at baseline they exhibit antiplatelet,
anticoagulant, and fibrinolytic properties.
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- On the other hand, they are capable (after injury or
activation) of exerting procoagulant functions
THROMBOSIS
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Three primary influences predispose to thrombus
formation, the so-called Virchow triad:
Endothelial injury
Physical loss of endothelium leads to:
- exposure of subendothelial collagen (and other
platelet activators)
- adherence of platelets
- release of tissue factor
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Dysfunctional endothelium may elaborate greater amounts
of procoagulant factors(e.g., adhesion molecules to bind
platelets, tissue factor, PAI, etc.) and smaller amounts of
anticoagulant effectors(e.g., thrombomodulin, PGI2, t-PA).
Abnormal blood flow
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Turbulence contributes to arterial and cardiac
thrombosis by causing endothelial injury or
dysfunction
Stasis is a major factor in the development of
venous thrombi
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Normal blood flow is laminar such that the platelet
elements flow centrally in the vessel lumen,
separated from the endothelium by a slower-moving
clear zone of plasma.
Stasis and turbulence therefore:
 a) Disrupt laminar flow & bring platelets into contact
with the endothelium
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b) Prevent dilution of activated clotting factors by
fresh-flowing blood
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c) Retard the inflow of clotting factor inhibitors and
permit the build-up of thrombi
d) Promote endothelial cell activation, predisposing to
local thrombosis, leukocyte adhesion, and a variety of
other endothelial cell effects
Examples: Myocardial infarction
HYPERCOAGULABILITY
STATES
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There are two general forms of
hypercoagulability states:
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conditions that create increased platelet
function and
conditions that cause accelerated activity
of the coagulation system.
Increased Platelet Function
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The causes of increased platelet
function are
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disturbances in flow,
endothelial damage, and
increased sensitivity of platelets to factors
that cause adhesiveness and aggregation
Hypercoagulability
Increased Clotting Activity
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results from factors that increase the
activation of the coagulation system,
including stasis of blood flow and
alterations in the coagulation
components of the blood (i.e., an
increase in procoagulation factors or a
decrease in anticoagulation factors)
Tips on thrombi
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Thrombi may develop anywhere in the cardiovascular
system: within the cardiac chambers, on valve cusps,
or in arteries, veins, or capillaries.
They are of variable size and shape, depending on
the site of origin and the circumstances leading to
their development.
Arterial or cardiac thrombi usually begin at a site of
endothelial injury or turbulence.
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Venous thrombi characteristically occur in sites of
stasis
The propagating tail may not be well attached and,
particularly in veins, is prone to fragment, creating an
embolus
Development of Coronary Atherosclerosis
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Coronary atherosclerosis is an inflammatory disease
characterized by the accumulation of white blood
cells, cell debris, fatty substances (cholesterol and
fatty acids), calcium, and fibrous tissue on the walls
of the coronary arteries that supply the heart muscle.
As plaque slowly increase in size over many years,
the artery narrows in places (stenosis), and blood
flow to the heart is reduced.
BLEEDING DISORDERS
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Bleeding disorders or impairment of
blood coagulation can result from
defects in any of the factors that
contribute to hemostasis.
Defects are associated with
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platelets,
coagulation factors, and
vascular integrity.
Platelet Defects
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Disorders of platelet plug formation
include
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a decrease in platelet numbers due to
inadequate platelet production (bone
marrow dysfunction),
excess platelet destruction
(thrombocytopenia),
abnormal platelet function
(thrombocytopathia), or
defects in von Willebrand factor.
Coagulation Defects
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Impairment of blood coagulation can result
from deficiencies of one or more of the
known clotting factors.
Deficiencies can arise because of
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defective synthesis,
inherited defects, or
increased consumption of the clotting factors.
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Bleeding that results from clotting factor
deficiency typically occurs after injury or
trauma.
Large bruises, hematomas, or
prolonged bleeding into the
gastrointestinal or urinary tracts or
joints are common.
Coagulation Defects
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Impaired Synthesis of Coagulation
Factors
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Hemophilia A
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factors V, VII, IX, X, XI, and XII;
prothrombin; and fibrinogen are
synthesized in the liver In liver disease,
synthesis of these clotting factors is
reduced
Deficiency or defect in factor VIII
Von Willebrand Disease
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Deficiency of or defect in vWF
results in reduced platelet adhesion
Disseminated Intravascular Coagulation
(DIC)
A variety of disorders ranging from obstetric complications to
advanced malignancy may be complicated by
disseminated intravascular coagulation:
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It is the sudden or insidious onset of widespread fibrin thrombi
in the microcirculation
While these thrombi are not usually visible on gross inspection,
they are readily apparent microscopically and can cause diffuse
circulatory insufficiency, particularly in the brain, lungs, heart,
and kidneys
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With the development of the multiple thrombi, there is a
rapid concurrent consumption of platelets and coagulation
proteins (hence the synonym consumption coagulopathy);
at the same time, fibrinolytic mechanisms are activated,
and as a result an initially thrombotic disorder can
evolve into a serious bleeding disorder
It should be emphasized that DIC is not a primary disease
but rather is a potential complication of any condition
DIC
EMBOLISM
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An embolus is a detached intravascular solid, liquid,
or gaseous mass that is carried by the blood to a site
distant from its point of origin.
Virtually 99% of all emboli represent some part of a
dislodged thrombus, hence the commonly used term
thromboembolism
Rare forms of emboli include droplets of fat, bubbles
of air or nitrogen, atherosclerotic debris (cholesterol
emboli), tumor fragments, bits of bone marrow, or
foreign bodies such as bullets.
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Emboli lodge in too small vessels, resulting in
partial or complete vascular occlusion. The
potential consequence of such thromboembolic
events is the ischemic necrosis of down-stream
tissue, known as infarction
INFARCTION
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An infarct is an area of ischemic necrosis caused
by occlusion of either the arterial supply or the
venous drainage in a particular tissue
Nearly 99% of all infarcts result from thrombotic or
embolic events, and almost all result from arterial
occlusion
Occasionally, infarction may also be caused by other
mechanisms, such as local vasospasm, extrinsic
compression of a vessel, for example, by tumor
Myocardial infarction
Coronary Angioplasty
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Coronary angioplasty is a procedure where a
narrowed section of a coronary artery is widened by
using a balloon and a stent attached to a catheter.
It is also known as percutaneous coronary
intervention (PCI).
A catheter is a thin, flexible tube which is inserted
into a coronary artery. The balloon at the tip of the
catheter is blown up at the narrowed section of
artery to force it wider. A 'stent' (a small tube) is left
in place to keep the artery widened.
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What is the mechanism of hemostasis?
the five step mechanism.
Explain in a diagram the intrinsic and
extrinsic pathway.
Explain the pathogenesis of
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Hemophillia A
Vonwillibrand disease
Conditions associated with
Hypercoagulability