Haemostasis and Thrombosis

Question 1

What percentage of Total Blood volume is Red Blood Cells?

Answer 1

45%

Question 2

What are the two functional types of Plasma Clotting Factors?

Answer 2

Procoagulants

Anticoagulants

Question 3

Name the main Procoadulant factors:

Answer 3

Fibrinogen - I

Prothrombin - II

Factors V, VII-XIII

Question 4

Name the main Anticoagulant factors:

Answer 4

Plasminogen

TFPI - Tissue factor pathway inhibitor

Proteins C & S

Antithrombin

Question 5

What is Haemostasis?

Answer 5

Physiological process that causes blood coagulation to prevent excessive blood loss

Question 6

What is Thrombosis?

Answer 6

A Pathophysiological process where a blood clot forms within a blood vessel and obstructs blood flow

Question 7

What are Red Thrombi?

Answer 7

Venous thromboses - contains lots of erythrocytes and fibrin

Question 8

What are White Thrombi?

Answer 8

Arterial thromboses - higher platelet component

They are white becuase of macrophages entering the lesion and becoming foam cells

Question 9

When does a clot become life-threatening?

Answer 9

If it dislodges from the vessel and embolises

Question 10

What is Virchow’s triad?

Answer 10

Three explanations for increased probability of Thrombus formation:

Rate of Blood Flow

Consistency of Blood

Blood Vessel Wall Integrity

Question 11

How can rate of blood flow lead to formation of a clot?

Answer 11

Slow blood flow increases likelihood of thrombosis especially in the leg because blood pressure is low here

Question 12

How can the consistency of blood affect the likelihood of a clot forming?

Answer 12

The balance between procoagulants and anticoagulants can change (especially in genetic conditions) and increase the chance - e.g. more pros and less antis

Question 13

How can Blood vessel wall integrity affect the likelihood of a clot forming?

Answer 13

Injury of the blood vessel wall (tunica intima) will expose prothrombotic subendothelial structures, which increase the likelihood of thrombi forming

Question 14

What are the three stages of Coagulation?

Answer 14

Initiation

Amplification

Propagation

Question 15

What are the three drug classes that target different stages of coagulation?

Answer 15

Initiation - Anticoagulants

Amplification - Antiplatelets

Propagation - Thrombolytics

Question 16

What takes place in the initiation stage of coagulation?

Answer 16

Initial Stage: small scale production of thrombin

A Tissue factor bearing cell (can be different types) in the lumen of a vein shows a tissue factor which activates Factors V & X forming the prothrombinase complex

The Prothrombinase complex converts prothrombin to thrombin

Question 17

What is the bodies normal response to the initiation stage of coagulation?

What happens in Pathological conditions?

Answer 17

Antithrombin (AT-III) is present within the blood and it inactivates factors IIa and Xa

Normally: Thrombin formed by prothrombinase complex, broken down by antithrombin

Pathologically: Too much thrombin may be formed

Question 18

Name the anticoagulants that may be used to prevent too much initial thrombin from being formed:

Answer 18

Dabigatran

Rivaroxaban

Heparin

Low molecular weight Heparins - Dalteparin

Warfarin

Question 19

What is Dabigatran?

Answer 19

Factor IIa inhibitor - Directly inhibits Thrombin

(oral)

Question 20

What is Rivaroxaban?

Answer 20

Direct inhibitor of Factor Xa - prevents activation of prothrombinase complex and therefore prevents production of Thrombin from Prothrombin

(Oral)

Question 21

What is Heparin?

Answer 21

Antithrombin potentiator - Activates AT-III reducing the amount of activation of factors II and X

(IV or SC)

Question 22

What is Dalteparin?

How do its actions compare to Heparin?

Answer 22

Low Molecular Weight Heparin

Antithrombin potentiator

Longer half-life than heparin

Activates the portion of AT-III that breaks down factor Xa more than IIa as seen in Heparin, so it’s pathway is more like Rivaroxaban

Question 23

What is Warfarin?

Why do its effects take some time to manifest?

Answer 23

Orally active Anticoagulant

Vitamin K antagonist (vitamin K epoxide reductase antagonist)

Vit-K is needed for generation of factors II, VII, IX and X

It stops production of these factors, but there is a reservoir in the blood which are used up first

Question 24

Label the Drugs that target the sites on this diagram:

Answer 24

Question 25

When may anticoagulants be clinically used?

Answer 25

To treat Venous Thromboses e.g. DVT and PE During Surgery to prevent blood clotting In Atrial Fibrillation to prevent stroke

Question 26

What happens in the Amplification stage of Coagulation?

Answer 26

Thrombin (which was activated by the Prothrombinase complex) interacts with platelets causing platelet activation The platelets change shape and become more sticky and they aggregate around the area of the thrombus formation

Question 27

How are platelets activated by Thrombin?

Answer 27

Thrombin binds to Protease-activated Receptor (**PAR**) PAR activation causes a release of Ca²⁺ from an internal store Calcium leads to exocytosis of **ADP** from granules, and makes them more sticky ADP has auto/paracrine effects - it binds to P2Y₁₂ receptors This causes liberation of **Arachidonic acid** and makes the platelets more activated and sticky **COX** (cyclo-oxygenase) converts Arachidonic acid to **Prostaglandins** and **Thromboxane A2** Thromboxane A2 increase expression of **GlpIIb/IIIa** on the surface - more sticky

Question 28

Name three antiplatelet drugs and show where they exert their effects on this diagram:

Answer 28

Clopidogrel Asprin Abciximab

Question 29

What is Clopidogrel?

Answer 29

P2Y₁₂ receptor antagonist Prevents platelet activation/aggregation

Question 30

What is Aspirin? | (In terms of Thrombosis)

Answer 30

Irreversible COX-1 Inhibitor Reduces the production of TXA2 from Arachidonic acid Reduces activity of platelets

Question 31

What is Abciximab?

Answer 31

Monoclonal antibody that is directed against GIpIIb/IIIa Reduces platelet aggregation (Specialist use only, and not commonly used because of effectiveness of Clopidogrel and Aspirin)

Question 32

When are Antiplatelets typically used clinically?

Answer 32

Arterial Thrombosis Acute coronary syndromes (e.g. MI) Atrial Fibrillation - Stroke prophylaxis

Question 33

What happens in the Propagation stage of coagulation?

Answer 33

There are now many activated platelets which cause a large-scale **thrombin** production on their surface Thrombin converts **Fibrinogen to Fibrin** Fibrin forms a net that traps the platelets within it

Question 34

What is the Thrombolytic drug used to bust clots of the Propagation stage? How does it work?

Answer 34

**Alteplase** (Recombinant type Plasminogen activator (rt-PA)) They convert Plasminogen to Plasmin, a protease that degrades fibrin

Question 35

What are the indications for Alteplase?

Answer 35

Indications: Arterial/Venous thromboses Stroke - first-line STEMI?

Question 36

Where are DVTs most likely to form, and what is done to prevent this pharmacologically?

Answer 36

Popliteal veins where there is stasis Prevented be restoring the balance of coags and anticoags Prophylactiaclly: anticoagulants e.g. Rivaroxaban After event like PE: Heparin

Question 37