CVS Lecture 13/14 - Haemostasis and Thrombosis Flashcards Preview

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Flashcards in CVS Lecture 13/14 - Haemostasis and Thrombosis Deck (55)
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1
Q

What are the functions of haemostasis?

A

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

2
Q

What is haemostasis important for?

A

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

3
Q

How is the haemostatic plug formed?

A

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

4
Q

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

A

Platelet adhesion, platelet aggregation

5
Q

How does platelet adhesion and aggregation occur?

A

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

6
Q

Where is von Willebrand made?

A

Endothelial cells

7
Q

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

A

Differing flow conditions in the vasculature

8
Q

What other ways can platelet activation occur?

A

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

9
Q

Where are platelets from?

A

Fragments of megakaryoctes -> half life of 10 days

10
Q

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

A

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

11
Q

Where are clotting factors, fibrinolytic factors and inhibitors synthesised?

A

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

12
Q

What is the blood coagulation cascade?

A

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

13
Q

What is the tissue factor?

A

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

14
Q

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

A

They localise and accelerate the reactions

15
Q

How does fibrinolysis occur?

A

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

16
Q

What are used for therapeutical thrombolysis for MI?

A

tPA and streptokinase

17
Q

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

A

Coagulation inhibitory mechanisms prevents this

18
Q

What are the 2 coagulation inhibitory mechanisms?

A

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

19
Q

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

A

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

20
Q

What does heparin do and what is it used for?

A

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

21
Q

What happens in the protein C pathway?

A

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

22
Q

What happens when coagulation inhibitory mechanisms fail?

A

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

23
Q

What is factor V Leiden?

A

Not so easily inactivated by Protein C

24
Q

How does the balance tip towards bleeding?

A

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

25
Q

What are the characteristics of abnormal bleeding?

A

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

26
Q

What is the response to injury to endothelial cell lining?

A
27
Q

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

A

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

28
Q

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

A

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

29
Q

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

A

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

30
Q

What are petechiae and what are they typical of?

A

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

31
Q

What is the main factor of the coagulation phase?

A

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

32
Q

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

A

Binds and stabilises platelet plug and other cells

33
Q

What is bleeding like in coagulation disorders?

A

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

34
Q

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

A

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)

35
Q

What is disseminated intravascular coagulation?

A

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

36
Q

What are the consequences of disseminated intravascular coagulation?

A

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

37
Q

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

A

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

38
Q

What are some symptoms in bleeding disorders?

A

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

39
Q

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

A

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

40
Q

What are some disorders of anticoagulant excess?

A

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

41
Q

What is thrombosis?

A

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

42
Q

What are the effects of thrombosis?

A

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]

43
Q

What is DVT?

A

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

44
Q

What is the prevalence of venous thrombo-embolism?

A

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

45
Q

Why do some people get thrombosis?

A

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

46
Q

Describe this graph

A

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

47
Q

What is Virchow’s triad?

A

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

48
Q

Which blood related factors increase the risk of thrombosis?

A

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

49
Q

What vessel wall related factors increase the risk of thrombosis?

A

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

50
Q

What flow related factors increase the risk of thrombosis?

A

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

51
Q

How do you identify thrombophilia?

A

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

52
Q

What are some other risks for thrombosis?

A

Pregnancy, malignancy, surgery, inflammatory response

53
Q

What treatment can be used to lyse clot?

A

tPA -> high risk of bleeding

54
Q

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

A

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

55
Q

What is the treatment and prevention of thrombosis?

A

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