Haemostasis

Question 1

What are the main steps in haemostasis?

Answer 1

Hemostasis has three major steps:

1) vasoconstriction,
2) temporary blockage of a break by a platelet plug, and
3) blood coagulation, or formation of a fibrin clot which stabilises the friable platelet plug into a stable clot.

Question 2

What is haemostasis?

Answer 2

Haemostasis is the stopping of haemorrhage. The word derives from the Greek words harm meaning blood and stasis meaning halt, i.e., halting the blood.

Question 3

How can haemostasis be helped?

Answer 3

Haemostasis can also be helped along therapeutically by means such as pressure to a bleeding point, suturing of an injury or application of a topical agent that aids clotting. These interventions slow down blood loss and allow the clotting process to take effect.

Question 4

What is clotting?

Answer 4

Clotting is the process whereby blood (a liquid in normal blood vessels) becomes a solid mass when it makes contact with connective tissue. It must not be allowed to happen inappropriately and it is controlled by an intricate system involving activation and inhibition
of clotting factors.

Question 5

What is the end result of the activation of the clotting system?

Answer 5

The production of the enzyme thrombin which acts on the circulating plasma protein fibrinogen (soluble) to
produce fibrin filaments (insoluble) which are then deposited and trap red blood cells.

Question 6

How are clots destroyed?

Answer 6

A parallel system called fibrinolysis destroys clots.

Question 7

Which type of cells can be in contact with blood and not clot?

Answer 7

Endothelial cells, white blood cells, unactivated

platelets and red blood cells.

Question 8

What is the first stage in haemostasis?

Answer 8

The severed artery contracts, not enough to stop the bleeding but enough to decrease the pressure downstream (contraction doesn’t occur in veins but the
pressure in them is much lower).

Question 9

What is the second stage in haemostasis?

Answer 9

A primary haemostatic plug of activated platelets forms at the hole in the vessel sticking to the injured vessel and the connective tissue outside it. This is fragile but
may control the bleeding. It forms in seconds to minutes.

Question 10

What is the third stage in haemostasis?

Answer 10

The secondary haemostatic plug forms as fibrin filaments stabilise the friable platelet plug into a blood clot. This forms in approximately 30 minutes.

Question 11

What are the three main players in haemostasis?

Answer 11

These are platelets, the process of blood clotting and the vascular wall.

Question 12

How are platelets activated?

Answer 12

Platelets are activated by a number of things. These include:
● Collagen surfaces (within extravascular areas)
● ADP (which is released by activated platelets and injured red blood cells and amplifies the platelet response)
● Thromboxane A2 (a powerful platelet aggregator which is also released by activated platelets)
● Thrombin (which informs platelets that the clotting sequence is activated).

Question 13

What happens to platelets once they are activated?

Answer 13

When platelets are activated they:
1. Stick to the exposed subendothelium (basement membrane or collagen) specifically to von Willebrand factor which is concentrated on the subendothelial basement
membrane.
2. Aggregate with other platelets. This is how the platelet plug, and then the secondary haemostatic plug, grows. Fibrinogen binds to the platelets and sticks them together.
3. Swell and change shape into sticky, spiny spheres.
4. Secrete factors from platelet granules that help the platelet plug to grow and aid clotting, e.g., some fibrinogen, ADP, thromboxane A2.

Question 14

How does aspirin decrease platelet aggregation?

Answer 14

Aspirin irreversibly inactivates cyclooxygenase, one of the enzymes responsible for the production of thromboxane A2. In this way it decreases platelet aggregation.

Question 15

What is the intrinsic pathway of blood clotting?

Answer 15

So called because it involves factors, all of which are contained within the blood. It is triggered by a negatively charged surface (e.g., the subendothelium or glass (it was first described by scientists experimenting with blood in glass test tubes) and no vessel needs to be broken open for it to occur.

Question 16

What is the extrinsic pathway of blood clotting?

Answer 16

So called because it needs a ‘tissue factor’ (thromboplastin, formerly called clotting factor III) which is present outside of the blood. This pathway is triggered by thromboplastin released from damaged cells adjacent to the area of haemorrhage.

Question 17

How does the vascular wall contribute to haemostasis?

Answer 17

The arterial media contracts when an artery is damaged and the subendothelium traps platelets. The endothelium actually performs a balancing act between opposing and favouring clotting, secreting substances such as tissue plasminogen activator and thrombomodulin (which interferes with the clotting cascade by activating protein C) that oppose clotting and substances such as von Willebrand factor and tissue factor (when it is damaged) that favour it.

Question 18

Which factors oppose clotting?

Answer 18

These include dilution of clotting factors by blood flow and natural anticoagulants. The later oppose the formation of fibrin (they don’t destroy it after it has been formed – that is fibrinolysis). The main natural anticoagulants are antithrombin III, protein C and protein S. If a person lacks any of these proteins they will experience repeated episodes of thrombosis.
Additionally, fibrin degradation products inhibit clotting.

Question 19

How does the clot evolve?

Answer 19

Platelets in the clot die. As they do so they cling to the fibrin and pull by their actin-myosin filaments in a mechanism which is basically the same as muscle contraction. This clot retraction helps in pulling together the sides of small wounds and may toughen the clot by
squeezing out fluid.

Question 20

How are clots destroyed?

Answer 20

Once the hole in the vessel has been repaired the blood clot is dissolved by fibrinolysis.

Question 21

How is fibrin broken down?

Answer 21

Fibrin has a built in short term obsolescence. Macrophages recognise it and break it down and it is destroyed by plasmin, the enzyme responsible for fibrinolysis.

Question 22

How is plasmin available in the blood?

Answer 22

Like thrombin, plasmin circulates as an inactive precursor. This is called plasminogen and it, like almost all the clotting factors and inhibitors, is made in the liver. It is activated by tissue plasminogen activator (tPA) which also circulates in the blood.

Question 23

How are plasminogen activators used therapeutically?

Answer 23

Plasminogen activators are used therapeutically as they dissolve fibrin and therefore thrombi and thromboemboli. A side effect of these drugs is, unsurprisingly, bleeding. This commonly occurs from the gums or nose but more seriously can occasionally occur in the brain.

Question 24

What initiates fibrinolysis?

Answer 24

It is actually the clotting cascade that sets fibrinolysis in motion as fibrin increases the activity of tissue plasminogen activator which produces plasmin which in turn breaks down fibrin to fibrin degradation products (FDPs, e.g., D-dimer).

Question 25

What causes an increase in FDP;s?

Answer 25

FDPs are increased in conditions where there is thrombosis such as disseminated intravascular coagulation, deep vein thrombosis and pulmonary embolism.

Question 26

Why is there an increased risk of postoperative thrombosis 7-10 days after surgery?

Answer 26

Importantly, after surgery fibrinolytic activity drops and remains low for 7-10 days, the time period that coincides with the increased risk of postoperative thrombosis.

Question 27

What is a clot replaced with?

Answer 27

The clot will eventually become organised (undergo fibrous repair) and be replaced initially by granulation tissue and then a tiny scar.

Question 28

How does haemophilia interfere with haemostasis?

Answer 28

People with haemophilia lack step 3 of the three steps of haemostasis. They have normal platelets but impaired clotting so they can’t produce an adequate amount of fibrin.

Question 29

What is Haemophilia A?

Answer 29

Haemophilia A is deficiency of factor VIII and is the most common hereditary disease associated with serious bleeding. It is an X-linked recessive disease. Patients have either a decreased amount or decreased activity of factor VIII. Treatment is infusion of
recombinant factor VIII.

Question 30

How do patients with Haemophilia A present?

Answer 30

Patients present with easy bruising and massive haemorrhage after trauma and surgery. “Spontaneous” haemorrhages occur in areas subject to minor trauma, e.g., joints (a haemorrhage into a joint is called a haemarthrosis). Recurrent bleeding into joints leads to
joint deformities. Petechiae (pinpoint haemorrhages) are not seen because they are caused by blood leaking from capillaries, which is typically the result of vasculitis or abnormalities in the number or function of platelets.

Question 31

What might you see from measure a patient with haemophilias blood?

Answer 31

A patient with haemophilia has a normal platelet count, bleeding time (as this is a measure of platelet activity), and PT but prolonged APTT (which measures the intrinsic pathway of which factor VIII is a part). They will have a low factor VIII assay.

Question 32

What is haemophilia B?

Answer 32

Haemophilia B is factor IX deficiency. It is clinically indistinguishable from haemophilia A and
like haemophilia A it is an X-linked recessive disease with variable clinical severity. Patients also have a normal platelet count, bleeding time and PT but prolonged APTT. It is treated with recombinant factor IX.

Question 33

What is Von Willebrand disease?

Answer 33

This is the most common inherited bleeding disorder. Patients with von Willebrand disease can vary from being asymptomatic to having a severe bleeding disorder. It is due to a deficiency or abnormality in von Willebrand factor. This protein has two functions. It assists in in platelet plug formation by attracting circulating platelets to sites of vessel damage and
it stabilises factor VIII protecting it from premature destruction. Bleeding time and APTT can therefore both be raised in the condition. The common pattern of bleeding is mucosal bleeding reflecting the inadequate platelet function and adhesion.

Question 34

What is thrombocytopenia?

Answer 34

A platelet count of less than 100 x 10 9 /L (normal = 150-400 x 10 9 /L) is classified as thrombocytopenia. Patients with such a low platelet count (or non-functional platelets) will lack step 2 of the three steps of haemostasis. In thrombocytopenia there is a prolonged bleeding time but normal PT and APTT (as these assess the clotting cascade and not platelet function).

Question 35

What are the symptoms of thrombocytopenia?

Answer 35

Spontaneous bleeding occurs with counts less than 20 x 10 9 /L. In thrombocytopenia spontaneous bleeding is seen from small vessels in places such as the
skin, gastrointestinal tract and genitourinary tract. Occasionally intracerebral bleeding can
occur. The bleeding appears as petechiae.

Question 36

What are the causes of thrombocytopenia?

Answer 36

The causes of thrombocytopenia can be classified as:

1. Decreased production of platelets – e.g., due to bone marrow infiltration by malignancy; drugs, e.g., cytotoxic drugs; infections, e.g,. measles and HIV; B12 and folate deficiency (which are needed for platelet production)
2. Decreased platelet survival – e.g., due to immunologic destruction, e.g., immune thrombocytopenic purpura; non-immunologic destruction, e.g., disseminated intravascular coagulation
3. Sequestration – in an enlarged spleen (hypersplenism)
4. Dilutional – due to massive blood transfusions (blood stored for more than 24 hours does not contain platelets).

Question 37

What is DIC?

Answer 37

Disseminated intravascular coagulation (DIC) is a thrombohaemorrhagic disorder occurring
as a secondary complication in a variety of conditions.

Question 38

What are the symptoms of DIC?

Answer 38

In DIC an activator of clotting gets into the blood and microthrombi are formed throughout the circulation. This process consumes platelets, fibrin and coagulation factors and activates fibrinolysis. The patient may then experience haemorrhage. It never occurs as a disease in itself but is always a complication of another condition, e.g., sepsis (especially gram negative sepsis as such bacteria produce endotoxin which activates
clotting), severe trauma (especially to the brain as it contains large amounts of thromboplastin), extensive burns, complications of childbirth (e.g., amniotic fluid embolism, retained dead foetus), malignancy, snake bite.

Question 39

How do you treat DIC?

Answer 39

Treat the underlying cause of the DIC. Otherwise, if bleeding is a prominent feature than transfusions
of platelets, fresh frozen plasma (FFP, which contains clotting factors), cryoprecipitates (which contain factor VIII, fibrinogen, von Willebrand factor and factor XIII), and red blood cells may well be needed. Occasionally treatment with an anticoagulant such as heparin is
required.

Question 40

What are the consequences of the microvascular thrombosis in DIC?

Answer 40

The microvascular thrombosis results in conditions such as neurological impairment, gangrene of the skin, renal failure, respiratory distress and gastrointestinal ulceration. The haemorrhagic component results in conditions such as intracerebral bleeding, petechiae,
haematuria, epistaxis and gastrointestinal bleeding.