Blood: L21 - Haemostasis and Blood Groups

Question 1

Name the process of formation of platelets (thrombocytes). What growth factor stimulates it?

Answer 1

Thrombopoiesis. Thrombopoietin.

Question 2

What is the function of platelets and why are they ideal cells for the function?

Answer 2

For haemostasis (stopping bleeding of an injured vessel), blooding clotting & coagulation. This is because of their ability to agglutinate, adhere and aggregate.

Question 3

Describe the 3 steps to haemostatic response.

Answer 3

1. Constriction of blood vessels (from vascular smooth muscle contraction) - an immediate but short lived response.
2. Formation of a platelet plug - platelets aggregate together at site of injury.
3. Formation of a haemostatic plug (blood clot): involves generation of fibrin via clotting pathways, which is added to the platelet plug.

Question 4

Discuss the positive feedback mechanism of platelet plug formation which shows blood vessels, platelets and blood coagulation system reacting together, starting with the change in endothelial surface of vessel.

Answer 4

Damage to a blood vessel leads to a change in the endothelial surface of that vessel: collagen is exposed.
This provides a surface for platelets to adhere to, and as they do so they change their conformation (to spiky and sticky), and become activated.
Activated platelets release a range of mediators including ADP, thromboxane and serotonin.
These mediators feed back to attract and activate more platelets, ultimately resulting in a clump of platelets at site of injury: the platelet plug.

Question 5

Describe what is tissue factor?

Answer 5

Tissue factor exposure is required for activation of the extrinsic pathway: Tissue factor is a cellular lipoprotein expressed by cells that are not normally exposed to flowing blood, and by cells that surround blood vessels. When tissues are injured, tissue factor will be exposed at the site of injury.

Question 6

What are the different clotting pathways, how do they get initiated and when do they become a common pathway?

Answer 6

The intrinsic clotting pathway is activated by collagen exposure, the extrinsic clotting pathway is activated by tissue factor, these pathways come together when factor X is activated.

Question 7

What is the general idea of what is happening between factors of the clotting pathways?

Answer 7

The pathways consist of a series of enzymatic steps in which an inactive enzyme is activated to its active form: a cascade of proteolytic (break down into smaller amino acid chains) reactions.

Question 8

Where do the proteolytic reactions take place? What factors are required for the reactions to occur?

Answer 8

These reactions occur on the surface of activated platelets, which provide the required binding sites and cofactors (such as calcium).

Question 9

Explain the intrinsic pathway and what is the condition called when certain factors are missing.

Answer 9

Begins when factor XII binds to exposed collagen fibres. Factors along the pathway include F XI (11), F IX (9), F XIII (8). Finishes at F X (10).
A lack of F VIII 8 causes the common Haemophilia A, while a lack of F IX 9 causes Haemophilia B.

Question 10

Describe the extrinsic pathway.

Answer 10

The extrinsic pathway is the main clotting pathway which occurs in the blood vessels. Begins with F VII (7) combines with tissue factor to form a complex. Finishes when this complex activates F X.

Question 11

Discuss the final common pathway.

Answer 11

Activated F Xa (resulting from either pathway) can activate prothrombin (aka F II 2) to thrombin (F IIa) by itself.
Thrombin activates fibrinogen (F I) to fibrin (F Ia), resulting in formation of a fibrin clot.
Activates F XIII, which is important for stabilisation of the fibrin clot: forms covalent bonds that allow the monomers of fibrin to be cross-linked together.
Activates factor V, which can combine with activated F Xa to form prothrombinase. Prothrombinase is better at activating prothrombin to thrombin than activated F X alone.

Question 12

Since haemostasis is too good and responsive, it must be limited so that it does not over do it’s job. What are some natural ways of limiting and opposing blood clotting?

Answer 12

Endothelial surface is smooth and prevents coagulation. Prostacyclin is produced by undamaged endothelium and inhibits platelet aggregation. Nitric oxide is also produced by endothelium and inhibits platelet aggregation and is also a vasodilator.

Question 13

What is ‘Tissue factor pathway inhibitor’?

Answer 13

TFPI is released from endothelium and binds to the tissue factor and factor VII complex, inhibiting the extrinsic pathway.

Question 14

How is thrombin inhibited?

Answer 14

1. By a protein found in plasma called antithrombin III binding to heparin (which would enhance the activity of antithrombins).
2. By binding to thrombomodulin.
   Both thrombomodulin and heparin are found on the endothelium.

Question 15

How do drugs inhibit clot formation?

Answer 15

Aspirin amongst other drugs inhibit platelet aggregation (preventing formation of a platelet plug) and therefore coagulation.

Question 16

What is the name of the process by which blood clots are dissolved? Explain the process of blood clot dissolving.

Answer 16

Fibrinolysis. Both ‘plasminogen’ and ‘tissue plasminogen activator’ (tPA) are incorporated into the blood clot as it is forming: at the same time as the clot is forming we are putting in what is needed to break it down.
tPA converts plasminogen to ‘plasmin’.
Plasmin breaks down fibrin strands into short and soluble fragments, leading to dissolution of the clot.

Question 17

Describe the fundamentals of blood transfusion.

Answer 17

Membrane proteins (antigens) are found on RBCs. These are genetically determined and heritable. Early on life we naturally develop antibodies to antigens not displayed on our RBCs due to sensitisation to environmental substances. Therefore cross-matching blood (according to ABO and rhesus classifications) before a blood transfusion is essential to avoid reactions between donor antigens and recipient antibodies.

Question 18

Describe the basis for the ABO blood grouping system.

Answer 18

3 genes = A,B,O produce antigens A or B (no product from “O”).
RBCs have antigen A or B alone, A + B or O (neither A nor B).
Have naturally occurring antibodies A and/or/neither B to antigen NOT present on own cells, which will attack any foreign antigens.

Question 19

What blood groups are universal donors and universal recipients?

Answer 19

Universal donors are O groups, universal recipients are AB groups.

Question 20

Why isn’t the ABO Blood grouping system useful in practice?

Answer 20

There are many other potential incompatibilities, and therefore cross-matching of potential donor and recipient blood has to proceed modern transfusion (checking for agglutination and destruction).

Question 21

Describe the Rhesus Blood group system.

Answer 21

There is another antigen present in the blood of about 85% of the population called the D antigen: individuals who have this are classified as Rhesus positive.
However, there are no pre-formed natural antibodies to the D antigen in Rhesus negative individuals.
Anti-Rh antibodies can slowly develop in Rh- individuals if they are transfused with Rh+ blood.

Question 22

When can consequences of the Rhesus system occur?

Answer 22

The D antigen can cause problems if a Rh- mother carries a fetus that is Rh+ (the D antigen is heritable, so this can occur if the father is Rh+): During birth some fetal RBCs cross the placenta; mother synthesizes anti-Rh antibodies but fortunately too late for the fetus to be affected.
Problem is in future pregnancies, mother’s anti-Rh antibodies cross placenta. If fetus Rh+ then RBCs destroyed by antibodies&raquo_space; anaemia and haemolytic disease of newborn.
Solution: Give mother anti-D antibody at first delivery to prevent antibody development.

Question 23

Is the ABO system a problem during pregnancy and why?

Answer 23

A and B antigens are not strongly expressed on fetal RBCs and the antibodies to these are of the IgM type that does not readily cross the placenta. (On the otherhand, anti-Rh antibodies are of the IgG type that does cross the placenta).