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CVS > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

Coagulation factors

A

Help clotting

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2
Q

Regulatory factors

A

Stop clotting

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3
Q

Haemostasis at rest

A

Factors+ cofactors= seperated

Triggers for clotting outside blood (collagen+ tissue factor)

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4
Q

vWF

Activation?

A

von Willebrand factor= Thrombulin
Biggest soluble protein in blood
Several binding sites
Normally= rolled up (binding sites aren’t exposed) but when bound to collagen, opens up through blood flow

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5
Q

Platelets are fragments of?

A 
Megakaryocytes (giant cells in bone marrow)
Granular structure (bigger than vWF)
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6
Q

Platelet structure

A

Sticky adhesive receptors:
Integrin αIIbβ3- binding site for it on the vWF
GP1ba complex- binding site for it on the vWF
GP1a-IIa - bind to collagen
GPVI complex- bind to collagen

Stimulatory receptors:
P2Y1- ADP binds to this (P= purine)
P2Y12- ADP binds to this
PAR 1 & 4- ADP binds to this
Thromboxane receptor- thromboxane binds to this
PGI2 receptor- Prostacyclin binds to this

Granules:
Dense granule
Alpha granule

Lysosyme
Mitochondria
Open canallicular system

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7
Q

Formation of a platelet plug- Primary haemostasis

When is this sufficient?

A
  1. Primary haemostasis- rolled up vWF gets stretched out and binds to collagen.
  2. Exposes binding sites to platelets so platelets bind to vWF
  3. Platelets get activated and release the granules which release more vWF which captures more platelets etc
  4. Fibrinogen helps link platelet/ vWF complex together
    Forms a platelet plug

Sufficient in small vessels (large vessels require secondary haemostasis)

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8
Q

Activated platelet

A

Change shape
Expose negatively charged phospholipid
Present new or activated proteins on their surface (i.e. GpIIb/IIIa)

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9
Q

Platelet binding

A

1) Platelet binds to vWF by GP1bα
2) When platelet slows down, can bind to collagen via GP1a-IIa+ GPVI too, and also to fibrinogen which binds it to other platelets via GPIIb-IIIa= causes Ca2+ INFLUX
3) Ca2+ influx causes activated GPIIb-IIIa+ degranulation which releases Fgn vWF (Fibrinogen vWF) and ADP
4) Ca2+ influx takes Phospholipid from the surface of the platelet (PLA2) and makes thromboxane (TXA2)
5) The release of ADP and thromboxane causes more platelets to come because receptors for ADP and thromboxane= activated (positive feedback event)

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10
Q 
Secondary haemostasis
Site of synthesis of molecules required in this process?
Process?
What is required?
What isn't required?
A

Liver (most of it)
Endothelial cells that line vessels themselves
Megakaryocytes

Tissue factor required
Collagen not required

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11
Q 
Secondary haemostasis PROCESS
Trigger?
Damping mechanism of trigger?
Draw? (slide 17, lecture 17)
What actually causes coagulation?
A

1) Trigger= tissue factor x VIIa complex formation
2) This turns zymogens 9 and 10 into active form (proteinase 9a and 10a)
3) Damping mechanism of trigger: TFPI= tissue factor pathway Inhibitor, which turns off the mechanism almost immidietaly by binding to 10a x tissue factor x VIIa to create an inactive complex
This means that this way of activating coagulation is turned off, but the 10a can make a little bit of thrombin
4) If you’ve made enough thrombin it will cause coagulation= conversion of fibrinogen (bulk protein in abundance in blood that is soluble) to fibrin (insoluble, forms a mesh)
5) If enough thrombin is made it will activate two other cofactors 5 and 8 into 5a and 8a, which help form 2 complexes:
a) 1st complex: Ca2+, 9a= enzyme, 8a= cofactor, PL= phospholipid the platelets are providing (link between primary and secondary haemostasis)
b) 2nd complex: 10a= enzyme, 5a= cofactor, PL, Ca2+
6) Extra feedback to make some 9 into 9a if needed
Result= amplification of thrombin production= platelet plug supported by fibrin mesh net that is cross linked by factor 13

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12
Q

Importance of thrombin production

A

Stronger, denser clot= more resistant to fibrinolysis
Factor XIII is activated by thrombin- cross links fibrin+ inhibits fibrinolysis
Thrombin activates TAFI = inhibitor of fibrinolysis

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13
Q

Anticoagulant function of endothelium

A

Proteins on surface of endothelium stop clotting in those areas (because the damage isn’t done there)
PGI2 and NO released from cells stop platelet activation
ADPase on membrane degrades ADP which stops the contribution of ADP in bringing more platelets etc to the site
Ensures clotting doesn’t occur everywhere

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14
Q

Inhibitory mechanisms of coagulation
Direct inhibition
Indirecti inhibition

A

Direct Inhibition: Deals with thrombin mainly
a) Antithrombin, inactivates XIa, IXa, Xa
Heparin makes the molecule more reactive and helps it and thrombin come together better
b) TFPI – in the initiation phase- damps down the 10a and 7a effect

Indirect inhibition: Deals with cofactors mainly
Inhibition of thrombin generation by the protein C anticoagulant pathway:
Thrombomodulin on endothelial membrane modulates thrombin’s activity.
1) Binds free thrombin and redirects thrombin activity from fibrinogen to protein C.
2) Activated Protein C + cofactor protein S down-regulates thrombin generation by degrading Va and VIIIa= stops thrombin production

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15
Q

Termination and localisation of coagulation

A

The thrombin that tries to get away causes APC production

Binds to Antithrombin which is either free floating or on heparan which is on endothelial membrane

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16
Q

Fibronolysis

A

1) tPA needs to meet Pgn to turn Pgn into plasmin, they meet on fibrin.
2) Plasmin is powerful enzyme that targets fibrin which forms FDPs (fibrin degradation products)
3) Antiplasmin stops the use of this outside the localised area

17
Q

Risk factors for thrombosis?

Genetics?

A

Deficiency of anticoagulant proteins:
Antithrombin deficiency
Protein C deficiency
Protein S deficiency

Increased coagulant proteins/activity: 
Factor VIII
Factor II & others
Factor V Leiden (increased activity due to activated protein C resistance)- hereditary defect, resistant to Protein C
Thrombocytosis (increased platelets)

Heterogenous genetic defect= viable
Homogenous genetic defect= death at birth

18
Q

SBA
Platelets
1.Bind to damaged endothelium through tissue factor.
2.Are inhibited by thromboxane.
3.Trigger coagulation at the site of injury.
4.Are activated and aggregate in response to ADP.
5.Have a life span of 100 days.

A

4

19
Q

Coagulation:

  1. FVIIIa is a protease, generated by thrombin.
  2. Factor XII interacts with tissue factor to initiate coagulation.
  3. Activated coagulation complexes assemble on the platelet surface.
  4. Fibrinogen must be converted to fibrin by thrombin in order to support platelet aggregation.
  5. FIXa is a cofactor that accelerates FX activation.
A

3

20
Q

Normal haemostasis

A 
Balance between:
Anticoagulant proteins: AT, PC, PS
Fibrinolytic factors: tPA, Pgn
Antiplatelet factors: PGI2
Endothelium: TM, EPCR, TFPI, Heparan
AND
Coagulation factors I-XI
Fibrinolysis inhibitors: AP, PAI-1, FXIII, TAFI
Platelets
Inflammatory mediators: IL-6, TNF
21
Q

Characteristics of abnormal bleeding

A

‘Spontaneous’
Out of proportion to the trauma/injury
Unduly prolonged
Restarts after appearing to stop

22
Q

Summary process of when you have an injury

A

1) Vessel constriction
Vascular smooth muscle cells contract locally
Limits blood flow to injured vessel
2) Primary Haemostasis: Formation of an unstable platelet plug
Platelet adhesion (vWF etc) + aggregation (ADP+ thromboxane)
Limits blood loss + provides surface for coagulation
3) Secondary Haemostasis: Stabilisation of the plug with fibrin
Blood coagulation
Stops blood loss
4) Fibrinolysis- Vessel repair and dissolution of clot
Cell migration/proliferation & fibrinolysis
Restores vessel integrity

23
Q

Defects of primary haemostasis (primary plug formation)

Examples of each?

A

Defective collagen- vessel wall (e.g.Steroid therapy, age, scurvy)

Defective Von Willebrand factor (e.g. Von Willebrand disease (genetic deficiency))
Platelets can’t stick- can’t bind to collagen if they go at speed
Can’t form the plug and even if the coagulation system works there is nothing for it to hold onto

Defective platelets (e.g. Aspirin & other drugs, Thromobocytopenia)

24
Q

Petichiae

A

Typical of thrombocytopenia
Pinprick type bleeding spots
Shows that vessels constantly break and reform

25
Q

Haemophilia

A

Primary haemostatic plug forms- stop bleeding to begin with, but it falls apart which is bad in large vessels
Problem in secondary haemostasis- not enough FVIII or FIX
Poor thrombin burst= poor fibrin mesh

26
Q

Defects of secondary haemostasis

A

Genetic:
Haemophilia: FVIII or FIX deficiency

Acquired:
a) Liver disease (most coagulation factors are made in the liver) e.g. cirrhosis
b) Drugs (warfarin – inhibits synthesis, other block function)
c) Dilution (results from volume replacement during trauma surgery- replaced RBCs but not the plasma with the coagulation factors= bleeding)
d) Consumption (DIC-disseminated intravascular coagulation) (acquired): Generalised activation of coagulation – Tissue factor inside vasculature
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors & platelets
Activation of fibrinolysis depletes fibrinogen
Widespread bleeding, from iv lines, bruising, internal
Deposition of fibrin in vessels causes organ failure

27
Q

Pattern of bleeding in primary vs secondary haemostasis disorders

A 
Primary= Immediate
Easy bruising
Nosebleeds (prolonged: >20 mins)
Gum bleeding (prolonged)
Menorrhagia (anaemia)
Bleeding after trauma/surgery

Secondary= Often delayed (after primary haemostasis)
Prolonged
Deeper: joints and muscles
Not from small cuts (primary haemostasis ok)
Nosebleeds rare
Bleeding after trauma/surgery
After i/m injections

28
Q

Easy bleeding

A

Ecchymosis

29
Q

Defects of clot stability: excess fibrinolysis

Examples?

A

1) Excess fibrinolytic (plasmin, tPA)
Therapeutic administration (for stroke/ embolus)
Some tumours

2) deficient antifibrinolytic (antiplasmin)
Antiplasmin deficiency (genetic)
30
Q

Unbalanced haemostasis – anticoagulant excess

Cause?

A

Usually due to therapeutic administration:
E.g. heparin or thrombin and Xa inhibitors
Activates antithrombin but makes them more prone to bleeding

31
Q

Thrombosis- what is it?
Effects? Artery vs Vein
Risk factors? Draw graph (slide 39, lecture 18)
How do genetic and acquired factors cause an increased risk of thrombosis?

A

Coagulation inside a blood vessel
Thrombi may be Venous or Arterial

Effects:
1) Obstructed flow of blood
Artery – myocardial infarction, stroke, limb ischaemia- more immediately serious
Vein – pain and swelling, e.g. DVT (Deep Vein Thrombosis)
2) Embolism – migration of the thrombus
Venous emboli, to lungs (pulmonary embolus)
Arterial emboli, usually from heart, may cause stroke (brain) or limb ischaemia

Risk factors
Interacting Genetic and Acquired Risk Factors (eg. injury/ pregnancy)
Age

Virchow’s Triad: may be inherited or acquired
blood- dominant in venous thrombosis
vessel wall- dominant in arterial thrombosis, expression altered in inflammation
flow- complex, contributes to both

32
Q

SBA:
A low plasma level of antithrombin is likely to result in:
1) Spontaneous haemorrhage
2) Prolonged bleeding after surgery
3) Myocardial infarction
d) An increased risk of post-operative thrombosis
e) Heparin hypersensitivity

A

d

33
Q 
SBA:
The increased risk of thrombosis associated with the COCP is likely to be the result of:
1) Factor V Leiden
2) Reduced concentration protein S
3) Reduced concentration of PAI-I
4) Reduced endothelial activation
5) Prolonged contact activation
A

b

34
Q

Treatment of thrombosis

A

1) lyse clot eg tPA (but high risk of bleeding)
2) Increase anticoagulant activity, e.g: adding heparin (immediate acting, parenteral)
3) Lower procoagulant factors, e.g.: warfarin (oral, slow acting for long term therapy, reduces ability of liver to make some coagulation factors)
4) Inhibit procoagulant factors– direct inhibitors Rivaroxaban (Xa), Apixaban (Xa), Dabigatran (IIa)

CVS (10 decks)

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