Cardio Block 8: Clotting

Define Haemostasis:

• stopping of bleeding

List the 3 phases of Haemostasis:

1. Vascular Phase

2. Platelet Phase

3. Coagulation Phase

What occurs during the Vascular Stage of Haemostasis?

1. injury to blood vessel wall triggers contraction is smooth muscle → decreases diameter of cut.

2. endothelial cells contract and expose underlying basement membrane to bloodstream → release chemical factors.

3. endothelial membrane becomes sticky and cells stick together to close cut

List 5 things that the endothelial cells release to the blood stream:

1. ADP

2. tissue factor

3. prostaglandin 12

4. endothelins

5. peptide hormones

List the effects of endothelins and peptide hormones:

1. stimulate smooth muscle contraction and promote vascular spasms (~30 mins)

2. stimulate the division of endothelial cells, smooth muscle fibres and fibroblasts to accelerate the repair process

What are platelets derived from?

• megakaryocytes (found in bone marrow)

How many platelets are found per microlitre of blood?

170,000 - 400,000

List what occurs during the Platelet Phase of Haemostasis:

1. damage to endothelium exposes collagen in the vessel wall

2. platelets bind to collagen via von Willebrand factor (vWF) → anchors platelets to the injury site

3. adhered platelets are activated (smooth discs → spiky form) + release chemicals from their granules

4. platelet aggregation occurs → temporary platelet plug forms

How long after initial injury does the Platelet phase begin?

• 15 seconds after injury

• thus overlaps with vascular phase

What is the collagen receptor to which platelets bind to called?

• glycoprotein Ia/IIa

In what complex does vWF circulate blood in?

• vWF + Factor VIII

List 5 chemicals that platelets release from their granules once activated:

1. ADP

2. thromboxane A2

3. serotonin

4. platelet-derived growth factor

5. calcium ions

List 3 functions of the chemicals from granules of platelets:

1. recruit more platelets

2. increase platelet stickiness

3. promote vasoconstriction

List 5 factors that limit growth of the platelet plug:

1. Prostacyclin; released by endothelial cells inhibits aggregation

2. inhibitory compounds released by other white blood cells

3. circulating enzymes break down ADP

4. negative feedback from serotonin

5. development of blood clot isolates area

Summarise what occurs during the coagulation phase:

• begins 30 seconds or more after injury

• blood clotting occurs

• cascade reactions

• chain reactions of enzymes and proenzyme

• converts circulating fibrinogen into soluble fibrin

List the 3 coagulation pathways:

1. Extrinsic

2. Intrinsic

3. Common

What occurs during the extrinsic pathway?

• begins in the vessel wall outside of bloodstream

• damaged endothelium releases → Factor III (tissue factor)

• TF + other compounds form an enzyme complex → activates Factor X

→ feeds into common pathway

What occurs during intrinsic pathway?

• begins with circulating proenzymes within bloodstream

• activation of factor XII when exposed to collagen

• platelets release factors (e.g. PF-3)

• series of reactions activates Factor X → feeds into common pathway

What happens during the common pathway:

• Where the intrinsic and extrinsic pathways converge

• Conversion of factor X to prothrombinase

• Converts prothrombin to thrombin

• Thrombin converts fibrinogen to fibrin

Which pathway is faster; extrinsic or intrinsic?

• extrinsic pathway is faster

• measured by prothrombin time

What is the role of thrombin in blood clotting?

1. thrombin converts fibrinogen → fibrin

2. stimulates formation of tissue factor → stimulates release of PF-3

→ forms a positive feedback loop (intrinsic and extrinsic)

→ accelerates clotting

List 5 substances which restrict blood clotting:

1. Anticoagulants

2. Heparin

3. Aspirin

4. Protein C

5. Prostacyclin

What releases heparin?

• basophils and mast cells

List 2 substances essential for clotting:

• calcium ions

• vitamin K

Why are calcium ions so important?

All 3 pathways for clotting require calcium ions; any disorder that lowers plasma Ca2+ concentrations will impair clotting

Why is vitamin K so important?

• vitamin K is needed in order for the liver to synthesise 4 of the clotting factors; prothrombin, factor VII, factor IX and factor X

Define Fibrinolysis:

• slow process of dissolving a clot

• thrombin and tissue plasminogen activator activates plasminogen

• plasminogen produces plasmin → digests fibrin strands

What is Virchow’s triad?

• Three broad categories of factors that influence the occurrence of thrombosis (clot)

• Too much clotting

List Virchow’s Triad:

1. Hypercoagulability; blood stuff

2. Vascular damage; blood vessel stuff

3. Circulatory stasis; blood flow

List 3 states in which hypercoagulability can occur:

1. after major surgery or trauma

2. late stages of pregnancy

3. inherited disorders like Ofelia

List 3 states in which vascular damage can cause too much clotting:

1. cellulitis (skin infection)

2. atherosclerosis

3. foreign objects being inside the vein

List 3 states where circulatory stasis can cause too much clotting:

1. immobility; high chances of venous obstructions

2. tumour obstructing veins

3. pregnancy; varicose veins

Define Prothrombin Time

• blood test used to evaluate clotting disorders

• measures how long it takes for blood to clot via the extrinsic and common coagulation pathways

What is a normal Prothrombin time?

• 11-15 seconds

Briefly summarise Prothrombin time test:

1. blood is obtained via venepuncture

2. blood is decalcified (so clotting doesn’t start before test)

3. centrifugation separates blood cells from plasma

4. Tissue factor is added to patient’s plasma (prothrombin → thrombin)

5. mixture is kept at 37 degrees for one to two minutes

6. calcium chloride is added → clotting starts

What is the International Normalised Ratio?

• PT is often standardized using INR, especially for patients on warfarin:

Normal INR ≈ 1.0

• Therapeutic range (e.g., in anticoagulation): ~2.0–3.0

What does the Prothrombin test indicate?

This test indicates a deficiency in any of the clotting factors 

Which test is used to measure the integrity of the intrinsic system?

activated partial thromboplastin time test ~ should be 35 seconds

List the intrinsic clotting factors:

• 12 (XII)

• 11 (XI)

• 9 (IX)

• 8 (VIII)

List the extrinsic clotting factors:

• factor VII (7)

• tissue factor (factor III)

List the common pathway clotting factors:

• Factor X (10)

• Factor V (5)

• Factor II (prothrombin)

• Factor I (fibrinogen)

• Factor XIII (13)

Would you expect to see a prolonged clotting time in a patient receiving anti-platelet drugs?

• no, you would not see a prolonged clotting time

• Anti-platelet drugs like aspirin or clopidogrel interfere with the platelets

• The coagulation cascade remains intact

• While the chemical clotting time is normal, the Bleeding Time (how long a physical wound actually leaks) will be prolonged.