Haemostasis, thrombosis, ischemia and infarction, and atherosclerosis
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Pathophysiology
Instelling
University Of Padua
Notes of pathophysiology.
Haemostasis: primary and secondary haemostasis with related disorders.
Thrombosis: pathophysiology, cardiac, venous, and arterial thrombi.
Ischemia and infarction: pathogenesis, risk factors, and types.
Atherosclerosis: pathogenesis, risk factors, and therapy
HAEMOSTASIS, THROMBOSIS, INFARCTION, AND ATHEROSCLEROSIS
GENERAL CONCEPTS
HAEMORRHAGES
DEFINITION
The haemostasis is a physiological process of the organism that stops bleeding. It does not block the
circulation in normal condition, but rather it acts in short time to block the blood loss and to avoid
further bleeding and shock. Therefore, the
haemostasis is efficient, fast, powerful, and
tightly controlled.
The endothelium is the main regulator of the
haemostatic balance; indeed, it releases several
factors that regulate the different steps of the
haemostasis (e. g. NO, PGI2, vWF, etc.). When
there are imbalances in the control of the
haemostasis two types of diseases may occur,
which are:
• Haemorrhagic diseases: they are
diseases that are caused by either
inefficient or lack of haemostasis; the
haemorrhage is the bleeding follow
vessel damage; the haemorrhagic
diathesis refers to the bleeding after
minor vascular damage; it may be
caused by fragility of vessels (e. g. scurvy, Marfan syndrome, etc.) and haemostatic disorders.
• Thrombotic disorders: they are caused by an excessive haemostasis; it corresponds to the
formation of a semisolid mass that adheres to the vessel wall; it can be caused by inborn
problems, acquired (e. g. atherosclerosis), and cancer.
HAEMORRHAGE FEATURES
The haemorrhages can be classified based on the location, the effects, and the results (or repair). The
location of haemorrhages can be of two types, which are:
• External: it occurs externally; it is the
most severe (e. g. bleeding after a car
accident).
• Internal: it occurs within the body cavity
or the body organs; an example is the
haemorrhagic effusion (e. g.
intramuscular); there are differences in
the internal bleeding, indeed:
Bleeding in the hollow organ: it
is more severe since there is not
any pressure that can stop the
blood loss (e. g. GI tract); an
example of GI tract
haemorrhage is caused by liver cirrhosis, which causes hypertension in the portal
vein; other examples are spleen rupture, aortic aneurysm, and oesophageal varices.
Bleeding in a solid organ: it is usually less severe since the pressure within the organ
can stop the bleeding (e. g. intramuscular bleeding).
The effects of bleeding can be of two types, which are:
• Acute haemorrhage: it causes hypovolemia, which in turn causes a decrease in the cardiac
output; the BP drops, and it may lead to shock.
, • Chronic haemorrhage: it causes anaemia (i. e. haemorrhagic anaemia); it may be caused by
peptic ulcer.
The local effects of blood loss depend on the site of the damage. The riskiest sites are the brain, in
which the cerebral haemorrhage may occur (compression decrease brain function), and the heart, in
which the pericardial effusion may arise (reduction in CO).
The result of bleeding is the development of an inflammatory process. After the recognition of PAMPs
and DAMPs there will be a regeneration and repair process. The repair will lead to scar formation
(there is not a restitutio ad integrum), which can be potentially harmful in some sites. Two examples
are:
• Joint ankylosis: it occurs in the joint after hemarthrosis.
• Ossifying myositis: it occurs in the muscle after muscular haematomas.
PHASES
The haemostasis is divided into four phases, which are:
• Vasoconstriction: it corresponds to a vascular spasm, which avoids the exit of blood from
vessels; it is a neurodegenerative
reflex that causes a fast contraction of
the smooth muscles.
• Platelet plug formation (or primary
haemostasis): it is divided into
adhesion, activation, aggregation,
and release of factors amplifying the
phenomenon; it is fast but weak.
• Coagulation (or secondary
haemostasis): it is an enzymatic
cascade which causes the conversion of fibrinogen into fibrin, thus forming the thrombus.
• Termination: it corresponds to the clot dissolution by plasmin upon repair of the vessel.
PLATELETS AND PRIMARY PLUG
PLATELETS FEATURES
The platelets are non-nucleated cells which derive from the megakaryocytes. Their half-life is of about
9-12 days, and their number is of about 150,000-450,000/L. Their number range a lot, differently
from the RBCs; this is due to the lack of a
negative feedback mechanism. While for
the RBC the negative feedback is provided
by the oxygen (high O2, decreased EPO
production), the only negative feedback for
platelets is given by thrombopoietin (TPO)
itself. When there are a lot of platelets, they
sequester the TPO to the megakaryocytes.
Conversely, with low platelets the TPO is
received by megakaryocytes, thus
increasing in platelet production.
The platelet activity is performed by the granules that are released by themselves. There are three
main granules, which are:
• -granules: they contain several factors involved in the coagulation; examples are factor V,
factor VIII, fibrinogen, vWF, thromboglobulin, platelet factor 4, and thrombospondin
(inhibitor of platelet aggregation).
• Dense granules: they contain serotonin, ADP, ATP (DAMPs in ECM), and calcium; note that
ATP and ADP act as signalling molecules in the ECM, and not as source of energy.
• Classical lysosomes: they are responsible for recycling the components of the platelets.
,VON WILLEBRAND FACTOR (vWF)
The von Willebrand factor (vWF) is an important protein that is involved in platelet adhesion and
activation. It presents two binding sites for collagen and two binding sites for integrins of platelets. It
is released by megakaryocytes and
endothelial cells; the latter store it into
the Weibel-Palade bodies (WPB).
The vWF is a monomeric protein of
250kD, but it is always present as a
dimer of 500kD in weight. The
dimerization is provided by three Cys
capable of creating disulphide bridges.
In circulation it associates with several
others vWF molecules; therefore, it forms a polymer of vWF with a high molecular weight. The
creation of this polymer ensures the possibility to associate with both several platelets and collagen
in short time.
PLATELET PLUG PHASES
The adhesion is the first process of the primary haemostasis, which is mediated by the vWF. During
this step, the GP1b present in platelet membrane binds to vWF, thus allowing the adhesion to the
exposed collagen. When the GP1b binds
to vWF, it triggers within platelets the
second and the third steps, which are the
activation and degranulation (i. e.
release), thus inducing the release of
platelet granules. Therefore, the vWF is
not important only for adhesion but also
for granule release.
During the degranulation, the ADP and
ATP that are release will cause an
amplification of the platelet response by
binding to their receptors (GPCRs, Gq).
Moreover, it causes the production of
thromboxane A2 (TXA2), which is a
derivative of arachidonic acid. Its main functions are to cause platelet activation and to induce a
localised vasoconstriction.
The secretion of granules changes the shape of platelets
(more stretched), as well as the affinity of integrins
present in their membrane (via calcium release). After the
degranulation, the integrins GpIIb/IIIa are more exposed
and present. This glycoprotein has a great affinity for
different substrates, in particular for the ones that contain
the consensus sequence Arg-Gly-Asp (R-G-D motif). One
of the most important substrates that contains this motif
is the fibrinogen.
As a result, platelets will
interact with fibrinogen
through their GPIIb/IIIa integrins, thus allowing the creation of bridges
between platelets. Once platelets are linked one with the other, the
platelet plug is formed, which contains fibrinogen inside. This will result
advantageous for the following coagulation process.
, ADAMTS13
The platelet plug must be stopped at a certain moment, otherwise it will continue to spread in the
blood vessel, and this may result in thrombi formation. The platelet plug is stopped by the ADAMTS13,
which is a protease that cleaves
the vWF in its A2 site, which is
found in the centre of the
protein (between Tyr1605-
Met1606).
The recognition and the
cleavage of the vWF in the A2
site occurs only during platelet
plug, during which the vWF is
stretched. Indeed, only when
the vWF is stretched the ADAMST13 can recognise the site and perform the cleavage. Therefore, the
recognition of the vWF only when it is stretched prevents the cleavage of it when it is free in
circulation. This is a self-limitation mechanism
performed by this protease.
To summarise, the primary haemostasis is divided
into four phases, the vWF allows the interaction of
platelets with collagen (1. Adhesion), the platelets
are activated (2. Activation) and release their
granules (3. Degranulation), and finally interact one
with the other through GPIIb/IIIa-fibrinogen
interaction (4. Aggregation). The last step consists
in the removal of the plug via ADAMST13 cleavage of vWF.
DEFECTS OF PRIMARY HAEMOSTASIS
THROMBOCYTOPENIA
CLASSIFICATION
The defects of primary haemostasis can be classified in three main types, which are:
• Qualitative alterations: they are caused by platelet dysfunctions; they can be either inborn
(e. g. Glanzmann disease, Bernard-Soulier
syndrome, etc.) or acquired (e. g. drugs,
infections, etc.).
• Quantitative alterations: they are caused by
change in the platelet number; the two main
alterations are thrombocytopenia and
thrombocytosis.
• Von Willebrand diseases: they are related to
quantitative or qualitative problems of the
vWF.
MANIFESTATION AND PLATELET PRODUCTION
The thrombocytopenia refers to a quantitative alteration of platelets, whose number is reduced below
150,000/L. It is manifested in different ways, according to the number of platelets. With a number
higher than 50,000/L the manifestations are often absent. Between 30,000-50,000/L bleeding upon
minor trauma occurs; with 10,000-30,000/L spontaneous cutaneous bleeding with generalised
purpura are observed; finally, with a number lower than 10,000/L spontaneous cutaneous and
mucosal bleeding, generalised purpura, and risk of CNS haemorrhages are observed.
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