Haemostasis and Vascular Pathology

Question 1

Define haemostasis

Answer 1

A precisely orchestrated series of regulatory processes that culminate in the formation of a blood clot that limits bleeding from an injured vessel.

Question 2

Define haemorrhage

Answer 2

Extravasation of blood into the extravascular space.

Question 3

Define thrombus

Answer 3

A solid mass of blood products in a vessel lumen.

Question 4

Define embolus

Answer 4

A detached intravascular solid, liquid or gas that is carried in the blood to a site distant from its point of origin.

Question 5

Define ischaemia

Answer 5

Tissue death due to inadequate blood supply.

Question 6

Define infarct

Answer 6

Inadequate flow of blood to a part of the body caused by constriction or blockage of the blood vessels supplying it.

Question 7

Describe the list of events initiated at a site of vascular injury to maintain normal haemostasis

Answer 7

1. Vasoconstriction - mediated by reflex neurogenic mechanisms and release of endothelin
2. Primary haemostasis - exposure of subendothelial von Willebrand Factor and collagen causes platelet binding and activation to form a platelet plug
3. Secondary haemostasis - exposure of subendothelial tissue factor which binds to factor 8 and initiates coagulation cascade. Thrombin cleaves fibrinogen to fibrin to form fibrin meshwork.
4. Clot stabilisation and reabsorption - platelets and fibrin aggregate to form a permanent plug

Question 8

What features do endothelial cells have that helps to maintain normal haemostasis?

Answer 8

Anticoagulant
Antiplatelet
Fibrinolytic

Acts as a barrier between thrombotic subendothelium and clotting factors in the blood.
Express factors that prevent thrombosis in undamaged vessels and limit clot formation to site of vascular injury.

Question 9

What is the role of platelets in haemostasis?

Answer 9

Form the initial haemostatic plug.
Provide a surface for recruitment and concentration of coagulation factors.

Three stages:

1) Adhesion to extracellular matrix at site of vascular injury
2) Activation by secretion of granules
3) Aggregation of platelets

Question 10

What is Virchow’s triad?

Answer 10

Factors that predispose to thrombosis:

Endothelial injury
Abnormal blood flow
Hypercoagulability

Question 11

How are the intrinsic and extrinsic pathways measured?

Answer 11

Extrinsic = prothrombin time (PT)

Intrinsic = Partial thromboplastin time (PTT)

Question 12

How can Virchow’s triad be used to explain the pathogenesis of thrombus?

Answer 12

Endothelial injury - main cause of arterial or intracardiac thrombi - clotting hindered by high levels of blood flow

Abnormal blood flow - either relative stasis ( slow flowing blood in veins - can cause DVT) or turbulent blood flow (occurs in arterial vessels - can cause AF)

Hypercoagulability - can be caused by inherited disorders or acquired disorders (e.g. dehydration, post op, carcinoma)

Question 13

What is the extrinsic pathway of the coagulation cascade?

Answer 13

1) Initiated by tissue factor
2) TF activates F7 and forms a complex with F7a and Calcium ions
3) Complex activates F9 and F10

[Leads to final common pathway]

Question 14

What is the intrinsic pathway of the coagulation cascade?

Answer 14

1) Initiated when F12 comes into contact with negatively charged surface (e.g. activated platelet)
2) F12 activated to F12a
3) F12a converts F11 to F11a
4) F11a converts F9 to F9a
5) F9a converts F8 to F8a
6) F9a, F8a and Calcium ions form complex which activates F10
7) Process amplified by downstream products such as F10a and thrombin

[Leads to final common pathway]

Question 15

What is the final common pathway of the coagulation cascade?

Answer 15

1) F10a, cofactor F5a and Calcium ions form a prothrombinase complex
2) Prothrombinase activates prothrombin and converts it to thrombin
3) Thrombin converts Fibrinogen to Fibrin
4) Fibrin monomers polymerise to form long fibres which form an insoluble network around the primary platelet plug
5) Clot further stabilised by F13a

Question 16

What factors would affect the clinical significance of a haemorrhage?

Answer 16

1. Volume of blood lost
2. Rate blood is lost
3. Medical fitness
4. Site of bleeding

Question 17

List the potential fates of thrombi

Answer 17

Propagation (enlargement)

Embolisation (detachment of thrombus to lodge at distant site)

Resolution (restoration of blood flow through degeneration of thrombus)

Organisation (channel formation in thrombus)

Question 18

What is an arterial thrombosis and its clinical significance?

Answer 18

Usually caused by endothelial injury and turbulent blood flow causing rupture of a plaque of atheroma

Occludes blood supply and can cause ischaemic necrosis (e.g. MI if thrombosis in coronary artery)

Question 19

Where are arterial thromboembolisms commonly found?

Answer 19

Lower extremities = limb ischaemia

Central nervous system = stroke

Intestines = bowel ischeamia

Kidney or spleen = often asymptomatic

Question 20

What are the risk factors for DVT?

Answer 20

Bed rest/ immobilisation (causes reduced muscle action and slow venous return - stasis)

Pregnancy (stasis due to enlarged uterus and hypercoagulability)

Post-surgical (stasis due to immobilisation, vascular injury and release of procoagulant factors)

Question 21

What is the function of the Fibrinolytic System?

Answer 21

Stabilises clot by activating Plasminogen into Plasmin (either by F12 dependent pathway or by plasminogen activators).
Plasmin breaks down Fibrin (thus stabilising clot by preventing it from getting too big) and contributes to its later dissolution.

Question 22

What are D-Dimers indicative of?

Answer 22

Hypercoagulability - a product of fibrin degradation

Question 23

How does Heparin affect coagulation?

Answer 23

Binds reversibly to anti-thrombin III thus enhancing its inactivation of Thrombin and FXa (preventing final common pathway of coagulation cascade)
2 forms: unfractionated Heparin which inactivates both FXa and Thrombin and low-molecular weight Heparin which inactivates primarily FXa

Question 24

When is Heparin usually used?

Answer 24

Prophylaxis and treatment of Venous Thromboembolism

Inhibits thrombosis in low doses and prevents progression of existing clots in high doses

Question 25

How does Warfarin affect coagulation?

Answer 25

Affects the metabolism of Vitamin K by inhibiting synthesis of Vitamin K-dependent coagulation factors (7,9,10 and prothrombin)

Question 26

When is Warfarin usually used?

Answer 26

Prophylaxis and treatment of Venous Thromboembolism and prevention of ischaemic stroke in AF

Question 27

How does Dabigatran affect coagulation?

Answer 27

Competitive, reversible inhibitor of Thrombin

a new oral anticoagulant

Question 28

Which coagulation factors require Vitamin K?

Answer 28

Factors VII, IX and X

Prothrombin

Question 29

What are coagulation cofactors?

Answer 29

Factors that accelerate reactions in the coagulation cascade

Factors V and VIII are both cofactors

Question 30

What are the functions of normal haemostasis?

Answer 30

Allows blood to be fluid in normal vessels

Allows formation of localised clot at site of vascular injury

Question 31

What is the consequence of failure of normal haemostasis?

Answer 31

Haemorrhage

Question 32

What is thrombosis?

Answer 32

A pathological process involving the formation of a solid mass of blood products in a vessel lumen potentially leading to vascular occlusion, infarction and/or ischaemia

Question 33

How do clinical consequences differ for thrombi formed in veins compared to arteries?

Answer 33

Venous thrombi = congestion and oedema

Arterial thrombi = ischaemia and infarction

Question 34

What are the potential symptoms of a DVT?

Answer 34

Swelling, pain, tenderness, erythema, increased temperature

Question 35

What is the route of embolism from DVT to PE?

Answer 35

DVT embolises and enters right side of heart before entering pulmonary circulation (pulmonary arteries) and entering lungs

Question 36

What are the signs and symptoms of a Pulmonary Embolism?

Answer 36

Shortness of breath, pleuritic pain, cough (+/- haemoptysis), tachycardia, tachypnoea, hypoxia

Can be asymptomatic
Sudden death if saddle embolus (affecting major pulmonary arteries)

Question 37

What factors limit coagulation?

Answer 37

Dilution (blood flowing past site of injury washes away activated coagulation factors which are then removed by liver)
Need for negatively charged surface (provided by activated platelets)
Anticoagulation factors (expressed by adjacent intact endothelium)
Circulating inhibitors (e.g. antithrombin III which inhibits FIXa, FXa, FXIa and FXIIa)
Fibrinolytic cascade