Haemostasis

Question 1

Normal haemostasis

Answer 1

Blood flows within the vascular system transporting oxygen nutrients and hormonal information around body. Dependant on balancing factors constituting coagulation factors and platelets

Question 2

Why is balance of blood constituents important

Answer 2

1)coagulation-allow stimulation of blood clotting processes following injury when blood changes from liquid state
2)thrombosis-limit extent of response to the area of injury to prevent excessive or generalized blood clotting
3)fibrinolysis-start process that breaks down the clot as part of the healing process

Question 3

What is an overall view of the Haemolysis

Answer 3

Halting of blood trauma to blood vessels has 3 processes
1)vasoconstriction of blood vessels
2)primary haemostasis formation of an unstable platelet plug at the site of vessel wall damage
3)secondary haemostasis stabilization of the plug with fibrin
Then fibrinolysis happens

Question 4

Why is it important to understand homeostatic mechanisms medically

Answer 4

Diagnose and treat bleeding disorders
Monitor drugs used to treat bleeding
Indetify thrombosis risks
Control bleeding in individuals who don’t have an underlying dirosder or blood

Question 5

Vasoconstriction of primary haemostasis

Answer 5

Nitric oxide and prostacylin (vasodilators) concentrations are less than endothelin (vasoconstriction) concentration reducing the amount of blood being lost

Question 6

What are platelets

Answer 6

Discoid,non nucleated,granule containing cells derived from myeloid stem cells
Formed in bone marrow by fragmentation of megakaryocyte cytoplasm and circulate for 10 days
Plasma membrane contains glycoproteins

Question 7

How do platelets react following injury to vessel wall

Answer 7

Stick damaged endothelium either directly to collagen via the platelet GPIa receptor or indirectly by the von willer brand factor which binds to platelet GPIb receptor
Causes activation and change shape from disc to rounded form with spicules to encourage platelet to platelet interaction

Question 8

What do platelets do after being activated

Answer 8

They release the content of their storage granules
Alpha granules or dense granules
Contents include ADP,fibronegen,VWF

Question 9

What other chemicals do platelets produce

Answer 9

Prostaglandin thromboxane A2 from arachidonic acid which is derived from the cell membrane
Useful in platelet aggregation but is a vasoconstrictor
Activated platelets also produce calcium

Question 10

What does the release of ADO and generation of thromboxane A2 do

Answer 10

ADP binds to p2y12 receptor and thromboxane binds to thromboxane A2 receptor which has a positive feedback effect

Question 11

How does fibrinogen bind to platelets

Answer 11

Platelet activation causes a conformational change in the GPIIb/IIIa receptor (inside out), which provide binding sites for fibrinogen

This binding causes outside-in signalling which further activates the platelets

Fibrinogen has a key role in linking platelets together to form the platelet plug

Question 12

How is inappropriate platelet aggregation avoided

Answer 12

Active flow of blood and release of prostacylin (PG12)
Is a powerful vasodilator
Released by endothelial cells

Question 13

What does aspirin do an an antiplatelet drug

Answer 13

Inhibits the production of thromboxane A2 by irreversibly blocking the action of cyclo-oxygenase (COX), resulting in a reduction in platelet aggregation
Effect last for 7 days

Question 14

Why is prostacylin production less inhibited by COX action

Answer 14

endothelial cells are nucleated so can synthesise more COX whereas the non-nuclear platelet can’t

Question 15

How does clopidogrel work as an antiplatelet drug?

Answer 15

It irreversibly blocks the ADP receptor (P2Y12) on the platelet cell membrane

The effect of clopidogrel also lasts 7 days until new platelets have been produced

Question 16

What is von Willebrand factor (VWF) and what is it synthesised by

Answer 16

A glycoprotein synthesised by endothelial cells and megakaryocytes and circulates in plasma as multimers (proteins with >1 monomer) of different sizes

VWF mediates the adhesion of platelets to sites of injury and promotes platelet-platelet aggregation

-
Is a specific carrier for factor vIII

Question 17

Why and when is fibrin formation needed

Answer 17

The primary platelet plug is enough for small vessel injury but would fall apart in larger vessels, so fibrin formation is needed to stabilise the platelet plug

Question 18

Coagulation

Answer 18

Thrombin is generated which cleaves fibrinogen to generate a fibrin clot that stabilises the platelet plug

Question 19

Where are clotting factors made

Answer 19

Most are made in the liver
Factor VIII and VWF are made by endothelial cells
VWF is also made in megakaryocytes

Question 20

Which vitamins do some factors rely on

Answer 20

Vitamin K for carboxylation of their glutamic acid residues which is essential for their function

II (prothrombin), VII, IX and X are the factors

Question 21

• What is each step of coagulation characterised by?

Answer 21

The conversion of an inactive zymogen (proenzyme) into an active clotting factor by splitting 1/more peptide bonds and exposure of the enzyme active site

Question 22

What are 2 factors in coagulation

Answer 22

V and VIII

Question 23

Where do clotting factors work

Answer 23

On exposed phospholipid surfaces of platelets which help localize and accelerate these reactions

Question 24

Calcium ions role in secondary homeostasis

Answer 24

Important in binding of clotting factors to phospholipid surfaces of platelets

Question 25

What happens in the initiation phase

Answer 25

**Tissue factor (TF)** is exposed on the **surface of endothelial cells**, leukocytes and most extravascular cells in an area of tissue damage- TF is normally located at sites not usually exposed to blood normally, so **when blood encounters TF at the injury site, this initiates coagulation** TF makes factor **VII into VIIa** which leads to activation of factors **IX to IXa** and **X to Xa** This leads to **activation** of **factor II (prothrombin)** which generates a ****small initial amount of **factor IIa (thrombin)**

Question 26

Amplification phase

Answer 26

The small thrombin amount (IIa) mediates the activation of cofactors V into Va and VIII into VIIIa, factor XI into XIa and platelets

Question 27

What happens in the propagation phase

Answer 27

**Factor XI** converts **more factor IX to IXa**, **IXa and factor VIIIa**, amplifies the conversion of factor **X to Xa** leading to a **rapid burst** in **IIa** and therefore **thrombin generation** This cleaves the circulating **soluble fibrinogen** to form the **insoluble fibrin** clot

Question 28

Why are coagulation inhibitory mechanisms important

Answer 28

As they prevent blood from completely clotting which ensures coagulation is confined to site of injury

Question 29

How is antithrombin involved in coagulation inhibition

Answer 29

It **inactivates thrombin (IIa)** and **factor Xa** The action of antithrombin is potentiated by heparin- this occurs by the **binding of antithrombin** to **endothelial cell-associated heparins**

Question 30

What does heparin do

Answer 30

It's a mixture of glycosaminoglycan chains extracted from porcine mucosa and works indirectly by **binding to and potentiating the action of antithrombin** which **inactivates thrombin and factor Xa** Heparin ****is **administered intravenously** or by **subcutaneous injection** **Inactivation of thrombin requires larger chains of heparin to wrap around both antithrombin and thrombin**

Question 31

What does warfarin do

Answer 31

It's a vitamin K antagonist and works by interfering with protein carboxylation- this reduces synthesis of functional factors II, VII, IX and X by the liver Oral tablet and regular blood testing is needed Takes several days as it reduces synthesis of coagulation factors rather than inhibiting existing factors Derived from coumarin

Question 32

Direct oral anticoagulants

Answer 32

**Orally** available drugs that **directly inhibit** either **thrombin or factor Xa** **without the involvement of antithrombin** They usually **don't require monitoring**

Question 33

Fibrinolytic system

Answer 33

**Plasmin**, which circulates in its inactive zymogen form **plasminogen** It's **activated by tissue plasminogen activator (t-PA)** when **both t-PA and plasminogen** together **bind** to **lysine residues on fibrin** The breakdown of fibrin produces fibrin-degradation products (FDPs) Plasmin **isn't specific to fibrin** and also **breaks down fibrinogen** and **clotting factors Va and VIIIa** for example Plasmin is **inhibited by antiplasmin** which circulates in the blood, also inhibited by alpha-2-macroglobulin

Question 34

What does thrombolytic therapy entail

Answer 34

Thrombolytic agents like **recombinant t-PA** are given to **ischaemic stroke patients intravenously** to make **plasmin** and lyse clots- this is time dependent however so t-PA needs to be given to eligible patients ASAP, preferably within the first hour of onset of symptoms There's a **high risk of bleeding associated with use**

Question 35

Who can be given thrombolytic therapy

Answer 35

Patients with life threatening pulmonary emboli

Question 36

What does antifibrinolytic drug tranexamic do

Answer 36

It's a synthetic derivative of the amino acid lysine and binds to plasminogen which prevents plasminogen from binding to lysine residues on fibrin- this is competitive inhibition This prevents activation of plasminogen to plasmin which would lead to fibrinolysis Tranexamic acid is used to **treat bleeding in trauma** and surgical patients and patients with **inherited bleeding disorders** - Has a **similar structure to the amino acid lysine**, (synthetic derivative of the amino acid lysine) - **Binds to lysine binding sites on plasminogen**, which prevents plasminogen from binding to lysine residues on fibrin, thus acts as a **competitive inhibitor** - Which **prevents activation of plasminogen to plasmin** which would lead to fibrinolysis

Question 37

Intrinsic vs extrinsic model

Answer 37

Intrinsic-components in plasma factors IX, X, XI, XII and cofactors VIII and V Extrinsic-TF and factors VII, X and cofactor V

Question 38

Prothrombin time tests for

Answer 38

Integrity if the extrinsic pathways Blood collected to which sodium citrate is added which chelates calcium to prevent blood clotting Sample spun and recombinant thromboplastin added to citrates plasma with calcium to start clotting reaction

Question 39

When is PT prolonged

Answer 39

If there's a reduction in activity of factors VII, X, V, prothrombin or fibrinogen We see bleeding in factor VII deficiency

Question 40

Internalized normalized ratio

Answer 40

A correction for the different thromboplastin sources used by different labs when PT is used to monitor Vit K antagonist anticoagulant therapy like warfarin- this is so everyone can obtain the same INR result for a given sample irrespective of the source of thromboplastin.

Question 41

Activated partial thromboplastin tests for

Answer 41

Measures the integrity if the intrinsic pathways Performed by the contact activation of factor XII by a surface like glass/using a contact activator like silica or kaolin- this activator is added along with phospholipid to citrated plasma and then calcium- the time taken to clot is measured

Question 42

When is APTT prolonged

Answer 42

When there is a reduction in a single or multiple clotting factors

Question 43

In which 3 deficiencies do we see bleeding with an isolated prolonged APTT

Answer 43

Factor VIII deficiency (haemophilia A) Factor IX deficiency (haemophilia B) Factor XI deficiency

Question 44

In which deficiency is there non bleeding patients with an isolated prolonged APTT

Answer 44

factor XII

Question 45

What can lead it bleeding

Answer 45

Reduction in platelet number Reduction in function of platelets Reduction in coagulation factors due to congenital diseas or drugs,liver disease,DIC Increased fibrinolysis may be due to administration of thrombolytic therapy

Question 46

What so thrombosis

Answer 46

Formation of a blood clot within an intact vessel that occurs due to obstruction of blood flow

Question 47

What is Virchow's triad of contributory factors to thrombosis?

Answer 47

1) Blood- dominant in venous thrombosis 2) Vessel wall- dominant in arterial thrombosis 3) Blood flow- complex, contributes to both arterial and venous thrombosis -

Question 48

Which 3 changes in blood increase the risk of venous thrombosis

Answer 48

Reduced levels of anticoagulant proteins Reduced fibrinolytic activity eg inhibition of plasminogen activation through PAI2 by the placenta Increased levels of clotting factors or platelet

Question 49

Which factor increases during pregnancy

Answer 49

VIII

Question 50

Direct vs indirect inhibition

Answer 50

Direct-antithrombin,an inhibitor of thrombin Indirect-inhibition of thrombin generation by protein c and s anticoagulant pathways

Question 51

Primary haemostasis

Answer 51

1) endothelial injury where secretion of nitric oxide and prostaglandin stop and secretion of endothelin starts 2) damage to endothelial cells exposes collagen which release vin willebrand factor 3)platelet changes shape releases more von willerbrand factor,calcium,ADP,thromboxane A2. ADP binds to p2y12 and thromboxane binds to thromboxane A2 receptor in a positive feedback loop

Question 52

How does vitamin k deficiency affect PT and APTT

Answer 52

APTT is increased as vitamin k is needed to make factor 9 10 and 2 pT is increased as there is deufcuney of factor 7 and ten

Question 53

Severe haemophilia

Answer 53

Severe’ haemophilia refers to undetectable plasma levels of factor IX (haemophilia B) or factor VIII (haemophilia A) . Henry receives infusions of recombinant factor IX concentrate . These are known as prophylaxis, and reduce the risk of spontaneous bleeding, which he would be prone to given the severity of his disease

Question 54

Beta thalassemia

Answer 54

Autosomal recessive Affects beta chains of haemoglobin Causes microcytic anaemia as haemoglobin not produced efficiently Blood transfusion given