Thrombosis

Question 1

What is coagulation

Answer 1

Coagulation is an inflammatory response to injury that is initiated by a coagulation cascade that
prevents blood loss.

Question 2

How is blood loss prevented in coagulation

Answer 2

This is through sealing of the wound that is aided by vasodilation that delivers
inflammatory products to the wound

Question 3

What causes ischaemia of the brain

Answer 3

Ischaemia of the brain caused by embolic stroke either from
the carotids or the heart is an example of where coagulation can go wrong. The result is a region of
neuronal cell death due to lack of blood flow. This can be fatal or very debilitating.

Question 4

What can the body’s response to damage be split into

Answer 4

The body’s response to damage is divided into two parts; primary and secondary haemostasis.

Question 5

What is primary heamostasis

Answer 5

Primary haemostasis is the activation of platelets that cause them to come together and stick along
with RBCs to become a clot (aggregation).

Question 6

What is activated in secondary heamostasis

Answer 6

Fibrinogen is then activated in secondary haemostasis to

form a firmer more rigid fibrin clot that is cross linked and this replaces the initial blood clot.

Question 7

When fibrinogen is formed what does it convert to

Answer 7

Fibrinogen is converted to fibrin by the protease thrombin that is itself activated by a series of
upstream reactions. There is in fact a whole cascade of reactions that culminate in the activation of
fibrinogen to fibrin.

Question 8

What two processes occur due to low levels of thrombosis

Answer 8

Anticoagulants can prevent thrombosis whilst fibrinolysis breaks down the clots
and reverses them. These two processes in fact occur all the time in the body in response to low
levels of thrombosis.

Question 9

Where can thrombosis form

Answer 9

Thrombosis can be formed in arteries or veins with the event occurring in each type of vessel being
very different.

Question 10

How does arterial thrombosis form

Answer 10

Arterial thrombosis mostly results from atheroma rupture or damage to the
endothelium. They tend to be platelet-rich mostly primary clots that can block downstream arteries.
This clot can in fact be dislodged and travel down to essential blood vessels in the lungs or in the
brain where the consequences are severe.

Question 11

How does venous thrombosis form

Answer 11

Venous thrombosis is the more serious type of thrombosis
due to them happening more often. They often result from stasis or hyper-coagulant state and the
clots formed are platelet-poor ‘red’ thrombus. They are mostly secondary clots and may move into
pulmonary circulation and block the lungs or even the heart itself.

Question 12

What must the body balance between - 2 processes

Answer 12

The body is constantly under the balance of coagulation and fibrinolysis.

Question 13

What factors does flowing blood interact with to initiate clotting

Answer 13

In a blood vessel, flowing
blood is surrounded by endothelial cells with a subendothelial layer of cells underneath this that are
not normally in contact with blood. When this layer is exposed, the blood interacts with tissue factor
(TF) that initiates clotting (comes into contact with factors in the blood). Blood can also interact with
von Willebrand factor that is also found in circulating blood, with the result of the interaction being
that platelets in the blood bind to this substance to start a clot.

Question 14

Why is a clot able to start without too much tissue damage

Answer 14

A clot can be started without too

much tissue damage due to the circulating von Willebrand factor (slowing down blood).

Question 15

What are the mechanisms that prevent blood from clotting

Answer 15

There are a
number of mechanisms by which blood clotting is prevented. Antithrombin and heparan binding
together inhibits clotting whilst prostaglandin I2 and nitric oxide (produced by the endothelium to
cause vasodilation) both inhibit platelets. There are all mechanisms to breakdown clots when they do
form.

Question 16

How are clots broken down

Answer 16

Tissue plasminogen activator activates plasminogen to become plasmin that then goes on to
act on clots and break them down into D-dimers (breakdown products).

Question 17

What three mechanisms are in balance

Answer 17

The mechanisms for clotting,

resisting clotting and reversing clots are all in balance.

Question 18

What does static blood lack and tend to do

Answer 18

Static blood lacks kinetic energy and tends to clot (lack of activity like patients in bed and
passengers in long haul flights).

Question 19

What can endothelial damage cause

Answer 19

Endothelial damage caused by surgery or a cannula can also cause
clotting as the subendothelial layer is exposed.

Question 20

What factors increase ones hyper- coagulation state

Answer 20

Factors that increase ones hyper-coagulant state
including infections (especially sepsis where the entire system becomes hyper-coagulant and this can
lead to death), genetic predisposition and drugs (e.g. HRT and oestrogen) all increase clotting.

Question 21

What increases risk of stasis in veins

Answer 21

Valves in the veins prevent the backflow of blood. Contraction of nearby muscles squashes
veins and acts as a pump tor return blood to the heart. Blood near the valves tends to eddy
around them increasing the risk of stasis (see right).

Question 22

What happens when venous return is eventually blocked - what is the name for this , risk

Answer 22

If venous return is eventually blocked,
the affected organ becomes congested with fluid increasing the pressure in the vein. This
increases the hydrostatic pressure pushing fluid out of the veins causing oedema. There
can also be some inflammation which amplifies the fluid build-up. This blockage is known
as deep vein thrombosis. The bigger risk is that the thrombus may become dislodged and
make its way back to the heart.

Question 23

WHat are the fates of thrombus

Answer 23

There are in fact several fates of the thrombus. The first is that the clot can be resolved by
thrombolysis.

This is in fact the fate of many micro-clots that are constantly being formed in our
bodies. The thrombus can sometimes become an embolism which is where it breaks off from the
wall of the endothelium and moves to another location to block that blood vessel (usually a smaller
vessel). This can be very serious depending on where the clot has settled. If it goes to the brain for
example, embolic stroke can occur whilst if it blocks part of the heart, this can also cause a serious
problems.

Question 24

What can happen if the thrombus is small

Answer 24

If the thrombus is small, it can sometimes become organised which is where the
endothelium grows over it. This is also very common and the effect is the blood vessel is a little
narrower and less elastic, however the consequences of this are minimal.

Question 25

What can happen to a very bad thrombus

Answer 25

Finally, if the thrombus is
very bad, it can be recanalised which is where the blood forces its way through and makes holes in
the clot. This thrombus can then become organised as well (new vessel with holes in it).

Question 26

What are the different types of thrombosis - describe

Answer 26

Deep vein thrombosis (DVT) can be proximal or distal depending on where it happens. Distal DVTs
are not very serious as they occur in smaller blood vessels in the lower part of the leg. They rarely
cause pulmonary embolism due to their small size.

Question 27

What is pulmonary embolism

Answer 27

Pulmonary embolism is where the clot is
dislodged, is moved into the heart and then pulmonary circulation where is becomes lodged in one
of the narrower vessels in the lungs.

Question 28

What can happen if proximal DVT occurs in upper leg

Answer 28

In proximal DVTs that occur in the upper
leg, there is a much higher risk of pulmonary embolism due to the larger size
of the clots that occurs in these larger vessels. Proximal DVTs are also at
much higher risk of causing post-thrombotic syndrome than distal DVTs.

Question 29

What is post-thrombotic syndrome

Answer 29

This
is where the clot does not move but in fact over time starves the tissue that
blood vessel serves (see right post-thrombotic syndrome). The result of this
is inflammation and damage to the valves from the thrombus itself which
can cause valvular incompetence.

Question 30

What can the persistent venous obstruction cause - symptoms

Answer 30

Persistent venous obstruction can also induce the rupturing of
small superficial veins that can cause subcutaneous haemorrhage and an increase in tissue
permeability. Symptoms include pain, swelling, discoloration and even ulceration.
The fate of the thrombus depends on its size.

Question 31

What can small venous thrombolus do

Answer 31

Small venous thrombolus is usually asymptomatic and
passes through the heart without any blockage and moves into the lungs where it can cause a small
infarction zone by blocking a smaller artery in the lungs.

Question 32

What can a large venous thrombolus do

Answer 32

A large venous thrombolus (found in a larger
artery like the femoral artery) can move into the heart and in fact, cause a saddle embolism where it
blocks both pulmonary arteries at the same time (worst case scenario and causes rapid death if it
happens). What is more common however is that it moves into one of the pulmonary arteries where
it then goes onto lodge in one of the lungs (this can still be serious however it does not lead to
immediate death).

Question 33

What initiates platelet adherence

Answer 33

Platelet adherence itself is normally initiated when it comes into contact with von Willebrand factor
found on the subendotheliam.

Question 34

When is the subendotheliam exposed

Answer 34

The subendotheliam is only exposed when there is damage to the
endothelium (tissue damage).

Question 35

What do activated platelets also bind to in order to attract more platelets

Answer 35

The activated platelets also bind to circulating von Willebrand factor
which in turn attracts more platelets to the site of injury.

Question 36

What can activated endocthelium a,so express

Answer 36

Activated endothelium calls can also

express von Willebrand factor.

Question 37

What do activated platelets release ( factors )

Answer 37

The activated platelets then release a number of different factors.
They release thromboxane A2 (TxA2) and adenosine diphosphate (ADP) that both induce receptors for
fibrinogen (these receptors are GPII/IIIa). The factors released behave in paracrine and autocrine
manners.

Question 38

What is paracrine activity

Answer 38

Paracrine activity is when a cell releases a substance that is received by the cell next door
causing a change that cell.

Question 39

What is autocrine activity

Answer 39

Autocrine activity is when a cell releases a substance that binds to itself
and causes a change that way.
This means the release of the factors causes the platelets that
released them to express more GPIIb/IIIa complex as well as other new platelets to be activated in
the same way. Platelets can also be activated by thrombin, collagen and many other mediators.

Question 40

After platelet activation what do platelets undergo

Answer 40

The next stage that platelets undergo is aggregation. This is where fibrinogen now involves itself with
the forming clot. Fibrinogen is in fact in circulation and when it associates with activated platelets, it
tethers and holds the platelets together (loose tether and not the final clot).

Question 41

What happens after platelets aggregate

Answer 41

The clump of platelets
formed form a negatively charged surface (caused by charged phospholipids) required for
coagulation. Coagulation itself is the conversion of the fibrinogen tethers into fibrin (much stronger)
in a protease reaction.

Question 42

What happens when fibrin builds up

Answer 42

Once the fibrin reaches a certain critical mass, it will be further cross-linked to
form a firm fibrin clot. The clotting cascade is what allows for the conversion of fibrinogen to fibrin
and for it to then be cross-linked.

Question 43

What are the three different coagulation pathways

Answer 43

There are 3 different coagulation pathways and these are intrinsic,
extrinsic and common.

Question 44

Describe the common coagulation pathway

Answer 44

The common pathway is the final part of the cascade. The conversion of
fibrinogen to fibrin requires thrombin. Circulating thrombin is not in an active form but is in fact in
the form of prothrombin. Prothrombin is activated by other coagulation factors (all proteases that
are activated in protease reactions). These factors can be formed from 2 different cascades, the
intrinsic or extrinsic pathways. The reason for this series of reactions is to amplify the number of
factors produced (i.e. 1 will activate 100 which will activate 1000000 etc). A second reason is to allow
for multiple steps where the process can be inhibited.

Question 45

What are the intrinsic and extrinsic pathways

Answer 45

The extrinsic pathway is activated by

trauma and is the most important one in vivo.

Question 46

How is the extrinsic pathway activated

Answer 46

The intrinsic and extrinsic pathways are the

two different ways the coagulation pathways are started.