Week 3 - A - Intro to Haemostasis - Platelet Plug (primary), Fibrin clot (secondary), fibrinolysis and natural anticoagulants (also P.T and A.P.T.T)

Question 1

What is homeostasis with regards to bleeding?

Answer 1

Homeostasis is the arrest of bleeding and the maintenance of vascular patency It ensures that clots can form in response to bleeding but once the bleed has ceased the clots are broken down to maintain patency Homeostasis with regards to bleeding is known as HAEMOSTASIS

Question 2

What are the 4 steps of haemostasis for bleeds?

Answer 2

Primary homeostasis -formation of the platelet plug Secondary homeostasis -formation of the fibrin plug Fibrinolysis Anti-coagulant defences

Question 3

What is primary homeostasis and when does this occur? What is secondary homeostasis and why does this occur? Why does fibrinolysis occur? and what is fibrinolysis?

Answer 3

First thing that happens when there is a bleed is - primay homeostasis this is where there is the formation of the platelet plug which stops small bleeds eg paper cuts In larger bleeds the platelet plugis not strong enough and secondary homeostasis is required for the formation of the fibrin clot - forms a solid mesh on surface of platelet plug Fibrinolysis occurs once bleeding ha stopped to maintain vascular patency - the clot is broken down

Question 4

How are platelets formed in the bone marrow?

Answer 4

Platelets are formed in the bone marrow by budding from megakaryocytes

Question 5

How does the platelets get from the megakaryocyte to the blood?

Answer 5

The megakaryocyte forms long branches known as proplatelets which extend through the fenestrated capillaries of the sinusoids so that they can drain into the central venous sinus in the marrow and out the marrow via the periosteal and nutrient veins and into the blood

Question 6

What is the lifespan of the platelet? What does a platelet look like? When there is damage to the endoethelium, how does this result in platelet adhesion? How does platelet aggregation occur?

Answer 6

The lifespan of a platelet is 7-10 days A platelet is a small anucleate disc When there is damage to the endothelium, this triggers the release of collagen and vWF which are important in causing the adherence of platelets to the damaged endothelium Once the platelets have adhered to the damaged endothelium they release various chemicals which leads to aggregation of platelets at the sit of injury

Question 7

Endothelial wall should be a complete vessel but if damaged this causes the release what substances that causes platelet adhesion to the site of injury? (just recapping previous card)

Answer 7

If there is vessel wall damage, collagen and von Willebrand factor are released which causes platelet adhesion

Question 8

What type of drugs can reduce the number of platelets? How do they cause failure of the platelet plug formation? What does a deficiency in vWF cause?

Answer 8

Anti-platelets eg aspirin reduce the number of platelets by inhibiting COX which prevents production of new platelets and platelet aggregation VWD means there is reduced vWF meaning platelet adhesion is not as efficient and also as vWF carried factor VIII in the blood, this will also be affected by its deficiency

Question 9

What are the consequences of failure of the platelet plug formation? (failure of primary and secondary haemostasis present differently)

Answer 9

There is usually spontaneous bruising and purprua Can have epistaxis, GI and conjunctival bleeds as well as menrrhagia Also if absolutely no platelets, then intracranial and retinal haemorrhages may occur

Question 10

What is the condition that is benign and occurs due to the decreasing collagen with age? This condition usually occurs in response to minor trauma causing bruising

Answer 10

This is senile purpura is a common, benign condition characterised by recurrent formation of purple ecchymoses (bruises) on the extensor surfaces of forearms following minor trauma. – due to collagen deficiency

Question 11

What is the one test that is used for the screening of primary haemostasis? What are the causes of failure of primary haemostasis again?

Answer 11

This would be measuring the platelet count Vascular - eg endothelial injury or collagen deficiency Platelets - low platelet number or reduced function Von willebrand factor deficiency (vWD)

Question 12

What is the inheritance on von willebrand disease mainly? (vWD)

Answer 12

Autosomal dominannt condition mostly

Question 13

What is secondary haemostasis? It provides stability for the platelet clot How does the platelet clot start of the secondary haemostasis formation?

Answer 13

Secondary haemostasis is the formation of the fibrin clot Once the platelet plug is formed, the platelets release phospholipid and calcium The phospholipid binds to the surface of the platelets and the calcium binds to this negatively charged phospholipid As calcium is positively charged this allows the nagtively charged clotting factors to bind starting the coagulation cascade

Question 14

What are the three different pathways in the coagulation cascade which result in fibrin clot formation?

Answer 14

This would be: The extrinsic pathway - requires the release of tissue factor by the damaged tissue The intrinsic pathway - the components are already present in the blood The common pathway

Question 15

The formation of the clot really occurs in three main steps - initiation, propagation and amplification What is released in response to a damaged endothelium and what does this act upon? Is this the extrinisc or intrinsic pathway?

Answer 15

Tissue factor is released in response to damaged endothelium which activates factors VII to make factor VIIa This is the extrinsic pathway

Question 16

TF/VIIa works on what clotting factors next? These are part of the common pathway of the coagulation cascade and what do these factors cause

Answer 16

TF/VIIa activate clotting factor X to Xa which in combination with factor Va goes on to convert prothrombin (Factor II) to thombin (Factor IIa) -

Question 17

What are the amplification effects that thrombin has on the coagulation cascade?

Answer 17

Thrombin releases factor VIII from vWF to which it normally circulates with and activates it to VIIIa. It also causes the activation of factor IX to IXa (does this by activating XI to XIa) - Both IXa and VIIIa increase activation of factor X to Xa increasing thrombin. Thrombin also increases V to Va.

Question 18

What is the final effect thrombin has to form the fibrin clot?

Answer 18

Thrombin cleaves fibrinogen (1a) to fibrin (1a)

Question 19

What are the clotting factors in the extrinisc pathway? What are the clotting factors in the intrinsic pathway? What are the clotting factors in the common pathway?

Answer 19

Extrinsic pathway clotting factors - Factor VII Intrinsic pathway - Factor VIII/IX (also XI/XII) Common pathway - Factor II (prothrombin), V/X and I (fibrin)

Question 20

Failure of the fibrin clot formation usually occurs from Single clotting factor deficiencies Multiple clotting factor deficiencies Increased fibrinolysis State conditions causing each of these?

Answer 20

Single clotting factor deficiencies are usually the haemophilias * Haemophilia A - Factor VIII deficiency * Haemophilia B - Factor IX deficiency Multiple clotting factor deficiencies * Dessminated intravascular coagulation (DIC) * All the clotting factors are made in the liver – Liver failure will therefore cause deficiency Increased fibrinolysis * usually part of complex coagulopathy

Question 21

What is the inheritance of haemophilia A and B?

Answer 21

These are x-linked recessive disorders

Question 22

Third part of haemaostasis is the breakdown of the fibrin blood clot How does fibrinolysis occur?

Answer 22

Tissue plasminogen activator (tPA) is released and this converts plasminogen to plasmin which promotes the breakdown of fibrin into fibrin degradation products

Question 23

What is the fibrin degradation product that is measured in the blot to see if there has been clot formation as the breakdwon of the clot will cause this to rise in the blood? If this substance isnt raised, is it usually still possible that there is a clot?

Answer 23

D-Dimers is the FDP that is measured in the blood Commonest use of D-dimers is when patients come in with a blood clot in a swollen leg – if forming a blood clot in a swollen leg it will immediately start to be broken down leading to D-dimer breakdown If youre D-dimer is low – basically have no blood clot (high sensitivity for clots, low specificity)

Question 24

In primary haemostasis, the characterisitc bleeding was spontaneous bruising and puprura - also epistaxis, GI bleeds or conjunctival or menorrhagia and if severe intracranial or retinal haemorrhages In secondary haemostasis the characteristic of the bleed depends on the type of bleed cause ie single or multiple clotting factor deficiencies If the patient has haemophilia, what is the characteristic bleeding?

Answer 24

If the patient has haemophilia it is characterisitc for the bleeding to occur into the joints (haemarthrosis) or muscles (haematoma) This person has haemophilia A – walked along and hit something Could not generate amplification as they do not have factor VIII and bled into the joint

Question 25

If the person has multiple clotting factor deficiencies, how is the bleeding characterised?

Answer 25

If there is multiple clotting factor deficiencies the bleeding tends to be far more generalised ie in DIC or liver disease

Question 26

What are the two main tests to look for fibrin clot reaction time?

Answer 26

These are measuring the prothrombin time and the activated partial thromboplastin time

Question 27

It is important when measuring the time for fibrin clot formation to fill the tube to the appropriate line on the tube – this is because at the bottom of the tube is citrate which is an anticoagulant –helps tokeep the blood from clotting before testing Does the PT or APTT measure the extrinisc pathway or intrinsic pathway? (which coagulation factors is it measuring)

Answer 27

PT - this is a measure of the extrinsic pathway - it evaluates clotting factors VII mainly APTT - this is a measure of the intrinsic pathway - it evaluates the intrinsic pathway - clotting factors VIII and IX mainly (but also XI and XII)

Question 28

Once we take blood to measure the PT or APTT time, what is added to start the clotting?

Answer 28

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Question 29

If someone has a very long PT or APTT, what clotting factors must the problem lie within? Which cause of primary haemostasis failure can affect the APTT?

Answer 29

Normal PT and APTT times depend on the reagent used by the lab (ie if they actually use thrombin and kaolin) PT - roughly 12 seconds APTT - roughly 30-40seconds * If someone has a PT problem, could be clotting factors VII, (as well as V,Xor II) * If someone has a APTT problem, could be clotting factors VIII,IX,XIorXII (as welll as X, II, I) * VWD causes primary haemostasis & prolonged APTT (platelet adhesion + binds factor VIII)

Question 30

What are the three naturally occuring anti-coagulants which prevent further clot formation in the blood once the bleeding has ceased?

Answer 30

This would be protein C, protein S and serine protease inhibitors

Question 31

What is one of the main serine protein inhibitors involved in anti-coagulation? What does it inhibit?

Answer 31

Anti-thrombin III (also known simply as anti-thrombin) which inhibits the action of various coagulation factors (mainly factors Xa, IIa, and to lesser extent IXa, XIa and XIIa)

Question 32

Once the clot has formed, a signal also goes out to thrombin changing its mechanism of action from promoting the amplification of coagulation via factors VIII/IXa. What does thrombin now do? Which anticoagulants does it promote the activity of? What are the main factors that these anticoagulant exert there effect on?

Answer 32

Once the fibrin clot has formed and bleeding has ceased, the thrombin now binds to thrombomodulin, a protein on the endoethelial surface and this then activates Protein C and S to start the anticoagulation process Protein CandS mainly work on factor V and VIII but do also work on various other clotting factors

Question 33

If there is a deficiency of the naturally occuring anti-coagulants this can result in what?

Answer 33

This can result in thrombophilia - the blood has an increased tendency to clot Will be discussed in thrombosis lecture