CVS Lecture 13/14 - Haemostasis and Thrombosis

Question 1

What are the functions of haemostasis?

Answer 1

Prevention of blood loss from intact vessels and arrest of bleeding from injured vessels

Question 2

What is haemostasis important for?

Answer 2

Diagnosis of bleeding disorders, treatment of bleeding disorders, ID of risks from thrombotic disease, treatment of thrombotic disease, monitoring of anticoagulant drugs

Question 3

How is the haemostatic plug formed?

Answer 3

Response to injury -> vessel constriction -> formation of unstable platelet plug -> stabilisation of plug with fibrin -> dissolution of clot and vessel repair

Question 4

What are the mechanisms for formation of an unstable platelet plug?

Answer 4

Platelet adhesion, platelet aggregation

Question 5

How does platelet adhesion and aggregation occur?

Answer 5

Endothelial cell damage reveals sub endothelial structures, such as collagen, which binds to von Willebrand factor (senses the damage) and then captures a platelet through Glycoprotein 1b -> PASSIVE. Platelets can also recognise the collagen and bind directly via Glycoprotein 1a -> PASSIVE. THEN, when receptors become engaged they signal and partially activate the platelet which releases ADP and TXA2 from storage granules -> which then causes platelet aggregation via Glycoprotein 2b/3a receptor on platelet which normally is hidden and needs ADP/TXA2 so that it can become active

Question 6

Where is von Willebrand made?

Answer 6

Endothelial cells

Question 7

Why are there several mechanisms by which platelets adhesion can occur?

Answer 7

Differing flow conditions in the vasculature

Question 8

What other ways can platelet activation occur?

Answer 8

Thrombin -> produced by coagulation activation; when thrombin further cleaves a certain receptor which further activates the platelet

Question 9

Where are platelets from?

Answer 9

Fragments of megakaryoctes -> half life of 10 days

Question 10

How does an activated platelet differ from a non-activated one?

Answer 10

Activated platelets change shape (round to pseudopodi and round shape), change membrane composition (important for fibrinogen attachment, coagulation occurs on the surface of the platelet), present new/activate proteins on their surface

Question 11

Where are clotting factors, fibrinolytic factors and inhibitors synthesised?

Answer 11

Liver, endothelial cells and megakaryocytes -> most in liver but some produced in high local concentration in endothelium (vWF) and megakaryocyte (factor V)

Question 12

What is the blood coagulation cascade?

Answer 12

All proteins as zymogen -> need to be activated. XIIa can be activated by endothelial surface (damage) -> VIIIa is a co-factor decreasing the time taken for X->Xa. Xa can be formed via enxtrinsic (tissue factors trigger factor VIIa to become activated and form Xa) and intrinsic pathway -> Xa converts protrhrombin to thrombin (which activates FVIII to FVIIIa so it can form even more thrombin, and FVa also undergoes this) -> the common pathway occurs on the surface of the cell

Question 13

What is the tissue factor?

Answer 13

It isn’t normally visible, as it forms a layer under the endothelium, so when there is damage to the vessel it becomes exposed and hence activates the clotting cascade -> TRIGGER for coagulation initiation

Question 14

What do the activated platelets help to do in the coagulation system?

Answer 14

They localise and accelerate the reactions

Question 15

How does fibrinolysis occur?

Answer 15

Tissue plasminogen activator (tPA) circulates inactively which when it comes into contact with a fibrin clot where it undergoes a conformational change and converts plasminogen to plasmin which starts to break down the clot, releasing fibrin degradation products

Question 16

What are used for therapeutical thrombolysis for MI?

Answer 16

tPA and streptokinase

Question 17

Why does blood not clot completely whenever clotting is initiated by vessel injury?

Answer 17

Coagulation inhibitory mechanisms prevents this

Question 18

What are the 2 coagulation inhibitory mechanisms?

Answer 18

1) Direct inhibition (antithrombin is inhibitor of thrombin/other clotting proteinases) 2) Indirect inhibition (of thrombin degradation by protein C anticoagulant pathway)

Question 19

Which are the coagulation proteinases and what does antithrombin do to them?

Answer 19

Inhibits them, forming an irreversible complex -> heparin makes antithrombin work faster. Coagulation proteinases are: Thrombin, Xa, IXa, XIa, XIIa, VIIa

Question 20

What does heparin do and what is it used for?

Answer 20

It accelerates the action of antithrombin -> used for immediate anti-coagulation in venous thrombosis and pulm embolism

Question 21

What happens in the protein C pathway?

Answer 21

Thrombin when coagulation is activated, binds to thrombomodulin, which then activates protein C which with Protein S (co-factor) and inactivate Factor Vai and VIIIai, so decrease synthesis of thrombin

Question 22

What happens when coagulation inhibitory mechanisms fail?

Answer 22

Antithrombin deficiency (inherited), Protein C/S deficiency and Factor V leiden -> all risks for thrombosis

Question 23

What is factor V Leiden?

Answer 23

Not so easily inactivated by Protein C

Question 24

How does the balance tip towards bleeding?

Answer 24

Too much activity from fibrinolytic factors and anticoagulant proteins; decreased activity of coagulation factors and platelets

Question 25

What are the characteristics of abnormal bleeding?

Answer 25

Spontaneous, out of proportion to the trauma/injury, unduly prolonged, restarts after appearing to stop

Question 26

What is the response to injury to endothelial cell lining?

Answer 26

Question 27

What are the main components in primary haemostasis and what are common examples of deficiencies or defective versions of these components?

Answer 27

Collagen -> steroid therapy, age, scurvy; von Willebrand factor -> vW diseases (genetic deficiency); Platelets -> aspirin and other drugs, thrombocytopenia

Question 28

What happens if there is a deficiency/defect of vWF?

Answer 28

Platelets aren’t captured, so there is failure of primary haemostasis

Question 29

What is the pattern of breathing for a patient with defects of primary haemostasis?

Answer 29

Immediate, easy bruising, nosebleeds (>20min), gum bleeding (prolonged), menorrhagia (anaemia), bleeding after trauma/surgery, petechiae

Question 30

What are petechiae and what are they typical of?

Answer 30

Red/purple spots under the skin due to bleeding -> typical of thrombocytopenia (deficiency of platelets in blood)

Question 31

What is the main factor of the coagulation phase?

Answer 31

Thrombin, which rises after a short lag phase in normal people until inhibited

Question 32

What is the function of the fibrin mesh that the platelets form?

Answer 32

Binds and stabilises platelet plug and other cells

Question 33

What is bleeding like in coagulation disorders?

Answer 33

Not enough fibrin is made, so in larger vessels the clot isn’t stable

Question 34

What are some common examples of defects/deficiencies in coagulation factors?

Answer 34

Genetic -> haemophilia (FVIII or FIX deficiency); Liver disease (acquired); drugs (wafarin - inhibits synthesis, other block functions); Dilution (from volume replacement); Consumption (disseminated intravascular coagulation - acquired)

Question 35

What is disseminated intravascular coagulation?

Answer 35

Generalised activation of coagulation -> tissue factor; associated with sepsis, major tissue damage, inflammation; consumes and depletes coagulation factors and platelets; activation of fibrinolysis depletes fibrinogens

Question 36

What are the consequences of disseminated intravascular coagulation?

Answer 36

Widespread bleeding, from IV lines, bruising, internal; deposition of fibrin in vessels causes organ failures

Question 37

What is the pattern of bleeding in secondary haemostasis disorders/defects?

Answer 37

Delayed and prolonged -> deeper in joints and muscles; not from small cuts (as primary haemostasis OK); nosebleeds rare; bleeding after trauma/surgery

Question 38

What are some symptoms in bleeding disorders?

Answer 38

Easy bruising (ecchymosis) - all bleeding disorders. Haemarthrosis - haemophilia hallmark

Question 39

What are 2 types of defects of excess fibrinolysis and some common examples?

Answer 39

Excess fibrinolytic (plasmin, tPA) -> therapeutic administration, some tumours. Deficient antifibrinolytic (antiplasmin) -> antiplasmin deficiency (genetic)

Question 40

What are some disorders of anticoagulant excess?

Answer 40

Usually due to therapeutic administration -> heparin, thrombin and Xa inhibitors

Question 41

What is thrombosis?

Answer 41

Intravascular/inappropriate coagulation, coagulation inside a blood vessel, not preceded by bleeding -> may be venous/arterial

Question 42

What are the effects of thrombosis?

Answer 42

Obstructed flow of blood -> artery [MI, stroke, limb ischemia], vein [pain and swelling]. Embolism -> venous [to lungs =PE], arterial [from heart, may cause stroke/limb ischemia]

Question 43

What is DVT?

Answer 43

Venous return of blood is obstructed -> painful, swollen leg -> can cause pulmonary embolism which causes sudden death sometimes

Question 44

What is the prevalence of venous thrombo-embolism?

Answer 44

Overall 1 in 1000-10000; increases with age -> PE causes 10% of hospital deaths; 5% case mortality

Question 45

Why do some people get thrombosis?

Answer 45

Genetic constitution, effect of age and previous events/illnesses/medication, acute stimuli

Question 46

Describe this graph

Answer 46

Different people start with different genetic risks, which then accumulate risks from environment and reach the thrombotic threshold

Question 47

What is Virchow’s triad?

Answer 47

3 contributary factors to thrombosis: Blood -> dom in venous thrombosis. Vessel wall -> dom in arterial thrombosis. Flow -> complex, contributing to both

Question 48

Which blood related factors increase the risk of thrombosis?

Answer 48

Deficiency of anticoagulatory proteins -> antithrombin, protein C/S. Increased coagulant proteins/activity -> factor VIII, II, V Leiden; thrombocytosis.

Question 49

What vessel wall related factors increase the risk of thrombosis?

Answer 49

Many proteins active in coagulation on surface of endothelial cells -> thrombomodulin, TF/pathway inhibitor; and the expression of these are altered in inflammation -> malignancy, infection, immune disorders

Question 50

What flow related factors increase the risk of thrombosis?

Answer 50

Reduced flow (stasis) increases the risk of venous thrombosis -> caused by surgery, fracture, long haul flight, bed rest

Question 51

How do you identify thrombophilia?

Answer 51

Thrombosis at young age, idiopathic thrombosis, multiple thromboses, thrombosis whilst anti-coagulated; lab can find identifiable cause of increased risk

Question 52

What are some other risks for thrombosis?

Answer 52

Pregnancy, malignancy, surgery, inflammatory response

Question 53

What treatment can be used to lyse clot?

Answer 53

tPA -> high risk of bleeding

Question 54

What treatment can be used to limit recurrence/extension/emboli?

Answer 54

Increase anticoagulant activity (heparin); lower procoagulant factors (warfarin); inhibit procoagulant factors - direct inhibitors (rivaroxaban/apixaban (Xa), dabigatran (IIa)

Question 55

What is the treatment and prevention of thrombosis?

Answer 55