Haemostasis (Session 5) Flashcards
What is haemostasis?
The stopping of haemmorage
How quickly does haemostasis act? To do what
Within seconds to prevent blood loss
What 3 processes does haemostasis involve and what are the 3 main players in haemostasis
1) Platelets -> - Platelet plug formation
2) The process of Blood clotting/coaulation cascade:
– Coagulation factors
– Anticoagulant factors
3) The vascular wall (endothelium) ->Vasoconstriction
Give 3 examples of how haemostasis can be helped along therapeutically
What do these interventions do?
- Pressure to a bleeding point
- Suturing of an injury
- Application of a topical agent that aids clotting.
These interventions slow down blood loss and allow the clotting process to take effect.
What is clotting?
The process whereby blood (a liquid in normal blood vessels) becomes a solid mass when it makes contact with connective tissue
When can problems arise with clotting?
When clotting occurs inappropriately
What is clotting controlled by?
an intricate system involving activation and inhibition of clotting factors
What is the end result of the activation of the clotting system?
- 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.
What system destroys clots?
What is this system parallel to?
- Fibrinolysis destroys clots
- Parallel to the clotting system
When will blood clot?
- As soon as it’s spilled from a vessel
Name cells that can be in contact with blood and not clot (4) - ASK ABOUT THIS
- Endothelial cells
- White blood cells
- Unactivated platelets
- Red blood cells
What state does blood need to be maintained in?
What does blood need to be able to do at the site of any vascular injury?
- a fluid clot-free state
- Needs to be able to produce a rapid and localised solid plug at the site of any vascular injury.
How many steps are involved in haemostsasis?
3
Describe step 1 of haemostasis
- The cut 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).
Describe step 2 in haemostasis
- 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.
Describe step 3 in haemostsasis
- The secondary haemostatic plug forms as fibrin filaments stabilise the friable platelet plug into
a blood clot. - This forms in approximately 30 minutes.
Describe the 3 steps of haemostasis
- 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). - 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. - The secondary haemostatic plug forms as fibrin filaments stabilise the friable platelet plug into
a blood clot. This forms in approximately 30 minutes.
Name 4 things that activate platelets
- Collagen surfaces (within extravascular areas)
- ADP
- Thromboxane A2
- Thrombin
1) What is ADP released by in the clotting cascade?
2) What does it do?
Released by activated platelets and injured red blood cells
2) Amplifies the platelet response
1) What is thromboxane A2?
2) What is it released by?
- Thromboxane A2 (a powerful platelet aggregator which is also released by activated platelets)
What does thrombin do?
- Informs platelets that the clotting sequence is activated
Describe the first thing that happens when platelets are activated
- Stick to the exposed subendothelium (basement membrane or collagen) specifically to von
Willebrand factor which is concentrated on the subendothelial basement membrane.
Describe the second thing that happens when platelets are activated
- 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.
Describe the third thing that happens when platelets are activated
- Swell and change shape into sticky, spiny spheres.
Describe the second fourth that happens when platelets are activated
- Secrete factors from platelet granules that help the platelet plug to grow and aid clotting, e.g.,
some fibrinogen, ADP, thromboxane A2.
Describe the 4 things that happen when platelets are activated
- Stick to the exposed subendothelium (basement membrane or collagen) specifically to von
Willebrand factor which is concentrated on the subendothelial basement membrane. - 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. - Swell and change shape into sticky, spiny spheres.
- Secrete factors from platelet granules that help the platelet plug to grow and aid clotting, e.g.,
some fibrinogen, ADP, thromboxane A2.
What drug can decrease platelet aggregation?
Aspirin
Describe how aspirin can decrease platelet aggregation
Aspirin irreversibly inactivates cyclooxygenase, one of the enzymes responsible for the production of thromboxane A2. In this way it decreases platelet aggregation.
In order for blood to clot, what needs to be produced?
What does the production of this mark?
- Fibrin needs to be produced
- This is the endpoint of the clotting cascade
Which enzyme cleaves fibrinogen to fibrin?
Thrombin
Does thrombin circulate in an active state?
Why or why not?
So what needs to happen to thrombin?
- It doesn’t because otherwise, blood will be solid
- It needs activated by a group of circulating molecules (clotting factors)
1) What are the clotting factors numbered from?
2) Which clotting factors are no longer used?
3) What do some clotting factors require for their synthesis ?
1) 1 to 13 (I to XIII)
2) 3 and 6 (III and VI
3) Vitamin K
Which clotting factors and anticoagulants require vitamin K for synthesis? (6)
- The clotting factors: II, VII, IX, X (2, 7, 9, 10)
- The anticoagulants protein C and protein S
What class do most clotting factors fall into?
Proenzymes
What do pro enzymes do?
each proenzyme activates the next in line and amplifies the effect.
What does effective clotting require?
Give 2 examples
- The presence of co-factors for the enzymes
E.g phospholipids and calcium
What do many of the interactions involved in clotting require?
What provides this?
- Many of the interactions involved in clotting require assembly of the components on a surface.
- This surface is provided by the platelet membranes when they swell and change shape during activation
How many pathways are involved in clotting?
Name them
- 2
- Intrinsic and extrinsic
- They act together
Why is the intrinsic pathway called the intrinsic pathway?
because it involves factors, all of which are contained within the blood.
1) What triggers the intrinsic pathway?
2) Give 2 examples
3) For it to occur, what doesn’t need to happen
1) A negatively charged surface
2) subendothelium or glass
3) no vessel needs to be broken open for it to occu
Why is the extrinsic pathway called the extrinsic pathway?
because it needs a ‘tissue factor’ (thromboplastin, formerly called clotting factor III) which is present outside of the blood.
What triggers the extrinsic pathway?
thromboplastin released from damaged cells adjacent to the area of haemorrhage.
1) Blood can even clot in the absence of…
2) But…
1) Platelets
2) Not as well
Describe the role of the vascular wall during clotting
- The vascular wall is not passive in haemostasis.
- 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, see below) that oppose clotting
- and substances such as von Willebrand factor and tissue factor (when it is damaged) that favour it
Describe 2 factors that oppose clotting
- Dilution of clotting factors by blood flow
- Natural anticoagulants
- Fibrin degradation products (inhibit clotting)
How do natural anticoagulants oppose clotting?
What don’t they do?
1) They oppose the formation of fibrin
2) They don’t destroy the clot after it has been formed (fibrinolysis does this)
1) Name the main natural anticoagulants
2) What happens if a person lacks any of these proteins
1) antithrombin III, protein C and protein S
2) they will experience repeated episodes of thrombosis.
1) What happens to platelets in the clot?
2) What happens as they do this?
3) What is this the same as?
1) They die
2) 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.
1) What happens once the whole in the vessel has been repaired?
- the blood clot is dissolved by fibrinolysis.
- 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.
What enzyme is responsible for fibrinolysis?
Plasmin
1) How does plasmin circulate the blood?
2) What is it called in this form?
1) As an inactive precursor
2) Plasminogen
1) Where is plasminogen made?
2) What activates plasminogen?
2) Name 2 other plasminogen activators
1) Liver
2) Tissue plasminogen activator (tPA), which also circulates in the blood
3) - Urokinase (a plasminogen factor found in urine)
- Streptokinase
Streptokinase is a plasminogen activator. Where is obtained from?
Thus where is streptokinase not usually present?
1) Streptococci
2) In the body
1) Why are plasminogen activators used therapeutically?
1) as they dissolve fibrin and therefore thrombi and thromboemboli.
1) What kind of molecule is streptokinase?
2) Thus how many times should the person be given it?
1) Antigenic
2) Only once
How many times can tissue plasminogen activator (tPA) be given to a person?
Why can it be given more than once but streptokinase can’t?
- More than once
- Because it has a higher affinity for fibrinogen than streptokinase and is not antigenic so it can be given more than once.
1) What is a side effect of streptokinase and tissue plasminogen activator?
2) Where does this occur?
1) Bleeding
2) Commonly from the gums or nose but more seriously can occasionally occur in the brain.
1) What sets the clotting cascade in motion?
2) Why?
1) The clotting cascade
2) 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)
When are FDP’s increased?
in conditions where there is thrombosis such as:
- Disseminated intravascular coagulation
- Deep vein thrombosis
- Pulmonary embolism
What happens fibrinolytic activity after surgery?
What does this time period coincide with?
- Fibrinolytic activity drops and remains low for 7-10 days
- coincides with the increased risk of postoperative thrombosis.
Describe the final fate of the clot
The clot will eventually become organised (undergo fibrous repair) and be replaced initially by granulation tissue and then a tiny scar.
1) What do people with haemophilia lack?
2) What is normal?
3) What is impaired?
4) So what can’t they do?
1) Lack step 3 of the 3 steps of haemostasis
2) Normal platelets
3) Impaired clotting
4) so they can’t produce an adequate amount of fibrin.
What is the most common hereditary disease associated with serious bleeding?
Haemophillia A
Describe the inherited disorder Haemophilia A
- Patients have either a decreased amount or decreased activity of factor VIII.
- X linked recessive (so affects males and homozygous females
Describe some symptoms of patients with haemophilia A
- Easy bruising
- Massive haemorrhage after trauma and surgery
- “Spontaneous” haemorrhages occur in areas subject to minor trauma, e.g. joints
What do you call a haemmorage in a joint?
haemarthrosis
What can recurrent bleeding into joints lead to?
- Joint deformities
What symptom is not seen in patients with haemophilia A?
Why not?
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
1) What is normal in a patient with Haemophillia A?
2) What is abnormal?
3) What will be low?
1) Normal platelet count, bleeding time (as this is a measure of platelet activity), and PT
2) Prolonged APTT (which measures the intrinsic pathway of which factor VIII is a part).
3) Factor VIII assay (Factor 8)
How is Haemophillia A treated?
infusion of recombinant factor VIII (8)
What is haemophilia B also known as?
Christmas disease
Deficiency of what factor leads to haemophilia B?
IX (9)
1) Is Haemophilia A clinically distinguishable from Haemophilia B?
2) What kind of genetic disease is haemophilia B?
1) No, they are clinically indistinguishable
2) X-linked recessive disease with variable clinical severity
1) What is normal in a patient with Haemophillia B?
2) What is abnormal?
1) Normal platelet count, bleeding time and PT
2) Prolonged APTT
How is haemophilia B treated?
Recombinant factor IX (9)
What is the most common inherited bleeding disorder?
Von Willebrand Disease
Describe the rang in symptom severity that can be seen in Von willebrand disease
can vary from being asymptomatic to having a severe bleeding disorder
What causes Von Willebrand Disease?
a deficiency or abnormality in von Willebrand factor
What are the 2 functions of the normal, functioning protein Von Willebrand factor?
- Assists in platelet plug formation by attracting circulating platelets to sites of vessel damage
- It stabilises factor VIII protecting it from premature destruction
What is raised in Von Willebrand Disease? (2)
Bleeding time and APTT
What is the common pattern of bleeding in Von Willebrand Disease and what does this reflect?
The common pattern of bleeding is mucosal bleeding reflecting the inadequate platelet function and adhesion.
What is the normal platelet count?
150-400 x 109/L
What platelet count is classified as thrombocytopenia?
count of less than 100 x 109/L
1) What occurs with platelet counts of less than
20 x 109/L?
2) What happens to such patients?
1) Spontaneous bleeding occurs
2) Patients with such a low platelet count (or non-functional platelets) will lack step 2 of the three steps of haemostasis
1) What is normal in a patient with Thrombocytopenia?
2) What is abnormal?
1) PT and APTT (as these assess the clotting cascade and not platelet function).
2) prolonged bleeding time
1) What is the main symptom of thrombocytopenia?
2) Occasionally, what can occur?
3) How does the bleeding appear?
1) spontaneous bleeding is seen from small vessels in places such as the skin, gastrointestinal tract and genitourinary tract.
2) intracerebral bleeding can occur.
3) petechiae
State the 4 main causes of thrombocytopenia
- Decreased production of platelets
- Decreased platelet survival
- Sequestration
- Dilutional
Describe Decreased production of platelets as a cause of thrombocytopenia (4)
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)
Describe decreased platelet survival as a cause of thrombocytopenia
e.g., due to:
- Immunologic destruction, e.g., immune thrombocytopenic purpura
- Non-immunologic destruction, e.g., disseminated intravascular coagulation
Describe sequestration as a cause of thrombocytopenia
Sequestration – in an enlarged spleen (hypersplenism)
Describe dilutional causes of thrombocytopenia
due to massive blood transfusions (blood stored for more than 24 hours does not contain platelets).
What does DIC stand for?
Disseminated intravascular coagulation
What is Disseminated intravascular coagulation (DIC)?
a thrombohaemorrhagic disorder occurring as a secondary complication in a variety of conditions
Describe what actually occurs 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.
What is a key symptom of DIC that a patient may experience?
Haemorrage
1) DIC never occurs as…
2) But as…
1) Never occurs as a disease in itself
2) Always as a complication of another condition
Give 6 examples of how DIC can occur secondary to another condition
It can occur secondary to:
- 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.
What is very important to remember when treating DIC?
To treat the underlying cause of DIC
If a patient is bleeding a lot from DIC (ie if we haven’t treated the underlying cause of the condition) , what may be needed?
- Transfusions of platelets
- Fresh frozen plasma (FFP, which contains clotting factors)
- Cryoprecipitates (which contain factor VIII, fibrinogen, von Willebrand factor and factor XIII),
- Red blood cells
What may be needed occasionally to treat DIC?
an anticoagulant such as heparin
Name 5 conditions that the microvascular thrombosis of DIC can result in
- Neurological impairment
- Gangrene of the skin
- Renal failure
- Respiratory distress
- Gastrointestinal ulceration
What conditions may the haemorrhagic component of DIC result in?
- Intracerebral bleeding
- Petechiae
- Haematuria
- Epistaxis
- Gastrointestinal bleeding
What can be measured in the blood of someone with DIC?
Why?
FDPs such as D-dimer can be measured in the blood because the fibrinolytic system is activated so those things are released in large numbers
What secondary condition can DIC result in?
Why?
- Microangiopathic haemolytic anaemia.
- Because Red blood cells are often traumatised and fragmented as they squeeze past the microthrombi.
What are thrombophillias?
inherited or acquired defects of haemostasis resulting in a predisposition to thrombosis, e.g., deep vein thrombosis.
Give 5 examples of thrombophillias
- Factor V Leiden (in which there is an abnormal factor V which isn’t deactivated resulting in thrombosis)
- Antithrombin deficiency
- Protein C or protein S deficiency
- Antiphospholipid syndrome.
