Haemostasis

Question 1

What is the haemostatic system

Answer 1

cascade/amplification system that stops the body from bleeding.
Haemostasis is a state of equilibrium between fibrinolytic factors, anticoagulant proteins, coagulation factors and platelets

Question 2

What are some factors associated with haemostasis

Answer 2

Von Willebrand factor

Platelets

Question 3

What state are factors and co factors at rest

Answer 3

They are separated

Question 4

Describe VWF

Answer 4

Very large and sticky protein with multiple binding sites

Largest protein in the blood

Question 5

Describe platelets and their receptors

Answer 5

Fragments of megakaryocytes
Half of 10 days
Localise and accelerate reactions
GP1a
Thromboxane receptors
Purine receptors
VWF receptors

Question 6

Explain the process of platelet activation

Answer 6

1. change in shape
2. phospholipid is exposed
3. new or activated proteins are presented on the surface e.g. GpIIb/IIa

Question 7

Explain the process of platelet plug formation/primary haemostasis

Answer 7

1. Damaged vessel wall
2. The blood meets collagen and tissue factor outside the vessel
3. VWF becomes stretched out across the damaged wall
4. Platelets are captured when they roll by and attach to the VWF via their receptors
5. Fibrinogen release to form the primary platelet plug

Question 8

How do platelets bind

Answer 8

binds to VWF via Gp1b𝛼
Secondary binding to collagen via GpVI
Initiates activation
Aggregation with other platelets via GpIIb and fibrinogen
Ca2+ efflux
Granules in the collagen molecule degranulate to release VWF (alpha) and ADP (Dense)
Thromboxane A2 release

Question 9

Why are tissue factors and collagen outside sub endothelial tissue

Answer 9

Prevent constant activation of factors and co-factors

Question 10

What is required for primary haemostasis

Answer 10

Collagen
Platelets
VWF (initiator)

Question 11

What is the limitation of solely using primary haemostasis

Answer 11

Can only be used for small vessels as large vessels require stabilisation (fibrin)

Question 12

Describe secondary haemostasis

Answer 12

coagulation and formation of a fibrin mesh
Amplifies the initial stimulus to produce a burst of thrombin
Thrombin converts soluble fibrinogen into insoluble fibrin
cross-linked fibrin stabilises the primary platelet plug

Question 13

What is secondary haemostasis triggered by

Answer 13

Tissue factor

Question 14

What are some sites of clotting factor and fibrinolytic factors + inhibitors synthesis

Answer 14

liver
endothelial cells (VIII, VWF)
megakaryocytes

Question 15

Describe clotting factor, fibrinolytic factor and inhibitor synthesis

Answer 15

VIIa circulates the blood
Circulates the blood and converts zymogens to proteinases Fxa
Thrombin is produced, activation FV and FVIII
FXI converted to FIXa

Question 16

Where is the activation of FXII to FXIIa used

Answer 16

in vivo reaction used in diagnostic test

Question 17

What is the function of thrombin

Answer 17

A burst of thrombin is essential, generating a stronger, denser clot more resistant to fibrinolysis

Question 18

Describe thrombin action

Answer 18

Activates FXIII which cross link fibrin so it is more resistant to fibrinolysis
Activates TAFI, an inhibitor of fibrinolysis

Question 19

Why is it important to control FVIIa generation

Answer 19

A small amount of FVIIa will produce a large amount of thrombin

Question 20

Compare direct to indirect inhibition of thrombin generation

Answer 20

direct - antithrombin uses an inhibitor or thrombin and other clotting proteinases + TFPI in the initiation phase
indirect - inhibition of thrombin generation by protein C anticoagulant pathway

Question 21

Describe antithrombin

Answer 21

Direct inhibitor of thrombin + proteinases
XIa. IXa. Xa. IIa (thrombin)
Complex from Iia, heparin and AT

Question 22

Explain how protein C inhibits thrombin generation

Answer 22

1. Thrombomodulin binds to free thrombin
2. Thrombomodulin redirects activity from fibrinogen to protein C
3. Activated protein C + cofactor protein S down-regulates thrombin generation by degrading Va and VIIa

Question 23

Describe the termination and localisation of coagulation

Answer 23

Antithrombin binds to heparin on the surface of the vessel and binds to free thrombin

Question 24

What is fibrinolysis

Answer 24

The fibrinolytic system is activated by formation of fibrin

Generates plasmin to breakdown the fibrin clot

Question 25

Explain the process of fibrinolysis

Answer 25

1. Fibrin formation 2. Tissue plasminogen activator converts plasminogen to active plasmin 3. Plasmin starts to break down fibrin 4. Fibrin degradation products formed 5. Antiplasmin prevents over activation and degradation

Question 26

What is thrombosis and what are the causes

Answer 26

Coagulation inhibitory mechanism where there is an inappropriate clot formation antithrombin deficiency Protein C deficiency Protein S deficiency C

Question 27

What are the haemostatic mechanisms during bleeding

Answer 27

Coagulation factors and platelets decrease | Fibrinolytic factors and anticoagulant proteins increase

Question 28

Give the 4 stages of haemostasis plug formation

Answer 28

Vessel constriction Formation of an unstable platelet Stabilisation of the plug with fibrin Vessel repair and dissolution of the clot

Question 29

Explain the process of adhesion and aggregation

Answer 29

``` Platelet adhesion via GIpIb Platelet aggregation 1. Change in shape 2. Release of Ca2+ from the stores 3. ADP release from the dense granule, vWF from the alpha granule 4. Thromboxane release 5. Expression of GPIIb or IIIa 6. aggregation via GPIIb and fibrinogen ```

Question 30

Give an example of what causes deficiency or defect in collagen in the vessel wall

Answer 30

Steroid therapy Age Scurvy

Question 31

Give an example of what causes deficiency or defect of Von willebrand factor

Answer 31

Von Willebrand disease type 1 - Not enough Type 2 - incorrect vWF type 3 - none produced

Question 32

Give an example of what causes deficiency or defect of platelets

Answer 32

Aspirin and other drugs | Thrombocytopenia

Question 33

Describe primary haemostatic bleeding

Answer 33

Bleeding is not delayed May arise from defect or deficiency of collagen, VWF or platelets Many congenital and acquired causes Petechiae are typical of thrombocytopenia

Question 34

What is abnormal bleeding is characterised by

Answer 34

bleeding being spontaneous, prolonged or out of proportion to the injury

Question 35

What is the pattern of bleeding primary haemostasis fails due to VWF

Answer 35

``` platelets cannot bind to VWF, do not slow down and cannot bind to collagen Immediate Easy bruising Nosebleeds Gum bleeding Menorrhagia Bleeding after trauma/surgery Petechiae (thrombocytopenia) ```

Question 36

Give some causes of secondary haemostasis disorders

Answer 36

``` Defects of coagulation Genetic: Haemophilia Protein C or S deficiency Antithrombin deficiency Factor 5 Leiden ``` ``` Acquired: Liver disease Drugs Dilution Consumption ```

Question 37

Give the pattern of bleeding for defects in secondary haemostasis

Answer 37

``` Often delayed and prolonged Deeper, seen in joints and muscles Not from small cuts Nosebleeds are rare Bleeding after trauma or surgery After injections ```

Question 38

How do defects of coagulation come about

Answer 38

Deficiency or defect of coagulation factors which results in inadequate thrombin generation

Question 39

Describe haemophilia

Answer 39

Not enough FVIII (A) or FIX (B) Coagulation does not occur Hereditary Failure to generate fibrin to stabilise the platelet plug Spontaneous haemarthrosis is the hallmark of haemophilia (swollen, very painful) Making a small cut will stop bleeding in 10 minutes

Question 40

Describe disseminated intravascular coagulation

Answer 40

Tissue factors are expressed on the inner surface of the blood vessels Leads to activation of coagulation, consuming and depleting coagulation factors and platelets Activation of fibrinolysis depletes fibrinogen Associated with sepsis, major tissue damage, inflammation Widespread bleeding, from IV lines, bruising, internal Deposition of fibrin causes organ failure

Question 41

What proportions of deaths are caused by thombosis

Answer 41

10%

Question 42

What can thrombosis in arteries and veins cause

Answer 42

Artery - myocardial infarction, stroke, limb ischaemia | Vein - Pain and swelling

Question 43

What can embolism in the arteries and veins cause

Answer 43

``` Arterial emboli (usually the heart) - may cause stroke or limb ischaemia Venous emboli (lungs) - pulmonary embolus ```

Question 44

What are the risk factors for thrombosis

Answer 44

``` Breaking bones/ fracture Age Pregnancy Cancer thrombosis at a young age AT deficiency ```

Question 45

What is Virchow's triad

Answer 45

Helps classifies the factors that cause thrombosis Vessel wall - Endothelial injury Flow - Stasis (in the venous circulation) or turbulent blood flow (causes PEs) Blood - Blood hypercoagulability - genetic or acquired

Question 46

Explain how the vessel wall affects thrombosis risk

Answer 46

expression of proteins required for coagulation is altered during inflammation e.g. malignancy, infection, immune disorders

Question 47

Explain how blood affects thrombosis risk

Answer 47

Deficiency of anticoagulant proteins: Antithrombin, protein C, protein S increase in coagulant proteins

Question 48

Describe the therapy for thrombosis

Answer 48

Restore the balance of haemostasis Lyse the clot e.g. tPA Limit recurrence/ emboli by: Heparin - increasing anticoagulant activity Warfarin - lower procoagulant factors Rivaroxaban, apixaban - inhibit procoagulant factors

Question 49

How does the contraceptive pill affect haemostasis

Answer 49

The oestrogen in the combined contraceptive pill affects several coagulation proteins, most notably increasing factors VIII, X and XII. It reduced protein S (which has anticoagulant properties) and there is a general reduction in fibrinolytic activity. This is also seen in pregnancy.

Question 50

What is heparin used for

Answer 50

Immediate anticoagulation in venous thrombosis and pulmonary embolism Works with antithrombin to inhibit thrombin

Question 51

Describe the acquired causes of secondary haemostasis disorders

Answer 51

Liver disease - Less liver synthesis so less coagulation factors produced Drugs - Heparin (antithrombin) and warfarin (II, VII, IX, X synthesis inhibition) causes bleeding Dilution - Lower concentration of coagulation factors Consumption - Disseminated intravascular coagulation

Question 52

Describe the genetic causes of secondary haemostasis disorders

Answer 52

Haemophilia Antithrombin deficiency - no IIa breakdown Protein C/S deficiency - no FV and FVIII breakdown Factor 5 Leiden - polymorphism, resistant to breakdown by protein C

Question 53

What are some fibrinolytic disorders

Answer 53

``` Genetic: antiplasmin deficiency (-) ``` Acquired (+): Excessive administration of plasmin/tPA Tumour secreting plasmin