Platelets & Haemostasis

What is endothelium cell (endothelium)?

What is HAEMOSTASIS?

1) a process which causes bleeding to stop

• “Haemo” = blood + “stasis” = motionless

• Clotting + stopping blood from escaping vasculature

• keeps blood within a damaged blood vessel

• the opposite of haemostasis is haemorrhage

• Haemostasis is the first stage of wound healing

2) The endothelium secretes inhibitors of haemostasis

• When injured, the endothelium stops secreting inhibitors and instead secretes von Willebrand factor (which triggers clotting)

What are the three platelet-based pathways to repair blood vessels?

Virchow’s Triad: Venous Thrombosis

What is HAEMATOPOIESIS?

Megakaryocytes —→ Platelets

1) Megakaryocytes (very profilic) in bone marrow

2) Thrombocyte = platelet

3) Thrombocytopaenia = low platelet count in blood

• 4000 platelets / megakaryocyte

4) In blood normally:

• Platelet count is ~20X < RBCs

• Platelet size = 3 x 0.5 µm

How is platelets activated for haemostasis?

Platelets Cover Wound: Haemostatic plug

COAGULATION - making blood clot meshwork

1) Many clotting factors 

• All circulate as inactive precursors *E

• Factor Xa is activated version of Factor X

• Most are enzymes, which cleave other factors to activate them

• Factor V and Factor VIII are NOT enzymes,

• they are necessary co-factors allowing the enzymes to function

• V and VIII also are inactive initially

2) Initial activating factor is segregated

• “works like epoxy”: need A + B to clot.  A or B alone are “safe”

• Example: tissue factor is behind endothelial cells, while clotting factor precursors are in the blood

How can thrombosis occur spontaneously where blood flow is slow?

What is THROMBOSIS?

abnormal formation of clot locally

What is EMBOLISM?

abnormal migration of a clot (or other intravascular object eg. big blob of fat)

Coagulation Overview

How is thrombin activated?

1) Activated by Factor Xa, but poorly

2) Factor Va is a co-factor for Factor Xa

3) Together they activate Thrombin well

What are the three pathways to activate factor X —→ Xa

1) Extrinsic Xase

2) Intrinsic Xase

3) Thrombin also indirectly activates it

• Positive feedback

What is EXTRINXIC XASE and INTRINSIC XASE?

1) Extrinsic Xase = Tissue factor (under endothelium) + factor VIIa

2) Intrinsic Xase = Factor VIIIa + Factor IXa

Positive Feedback in coagulation

The Coagulation Factors - PROTHROMBIN GROUP

The Coagulation Factors - THROMBIN GROUP

Coagulation: What you need to know

1) The coagulation factors of the common pathway

2) That there are extrinsic and intrinsic pathways that feed into the common pathway

3) Coagulation is based on a positive feedback loop, where thrombin activates upstream clotting factor

4) What Factor VIII and Factor IX do, esp. for haemophilia

Where are clotting factors made?

1)Clotting factors are made by the liver

• Liver dysfunction, cirrhosis or hepatitis can —→ clotting deficiency

What is Vitamin K useful for?

1) A class of related fat-soluble vitamins

2) Is required to synthesize enzyme coagulation factors:

3) Prothrombin (II), VII, IX, X (calcium dependent proteases)

4) Vit K essential for gamma carboxylation of clotting enzymes

What is FIBRONOLYSIS and INHIBITION OF COAGULATION?

What is a PLASMIN?

1) Lyses fibrin – stops / destroys clots

2) Starts as inactive Plasminogen (an enzyme)

• Plasma protein made by liver

3) Requires tissue Plasminogen Activator (tPA) to mature

• tPA is on the surface of endothelial cells

What is PROTEIN C?

1) Coagulation Inhibitor

2) Starts as an inactive enzyme

• Made by liver

• Activated on surface of endothelial cells

3) Inactivates Factor Va & Factor VIIIa

• Works with a co-factor Protein S to inactivate Va

What is ANTITHROMBIN III (+ heparin)?

What is VITAMIN K deficiency?

What is HAEMOPHILIA A?

What is Haemophilia B?

1) Christmas disease defect is factor IX

• Also called “Haemophilia B”

• Symptoms as per Haemophilia A

Atherogenesis: A disease of inflammation

Atherogenesis: A disease of Lipids

Atherogenesis: A disease of the endothelium

1) Endothelium expresses chemoattractants

• For monocytes to find and enter lesion

2) When endothelium is lost, collagen stimulates coagulation

• Endothelium normally covers collagen and basement membrane

3) When endothelium is lost, vessel cannot control its dilation

• Endothelium normally provides nitric oxide

How can blood clotting be controlled pharmacologically?

1) Anti-platelet agents

• Block platelet activation

• Good for treating arterial disease *E

2) Anti-coagulants

• Block production or activity of clotting factors

• Used to treat venous disease *E

3) Fibrinolytics

• Also called Anti-thrombotics or ‘clot busting drugs’

• Primarily used to dissolve fibrin in arterial disease

What are ANTI-PLATELET AGENTS?

What are ANTI-COAGULANTS?

1) Prevent clotting in veins *E

• And in low pressure pulmonary circ

2) Prophylactic for:

• deep vein thrombosis

• Pulmonary embolism

What is NOACs?

1) Novel Oral Anti-Coagulants (NOACs)

• Dabigatran (thrombin inhibitor)

• Rivaroxaban (factor Xa inhibitor)

What are HEPARINS?

1) Inhibit coagulation (with AT III) by inhibiting Factor Xa

2) Different types of heparins

What are WARFARINS?

• Vitamin K antagonist

• Slow onset (days)

• Requires monitoring

What are the FIBRONOLYTICS (clot bursting)?

1) Clotting in arteries (high pressure)

2) Used during Acute Coronary Syndromes (eg AMI)

3) Tissue Plasminogen Activator (tPA)

• Streptokinase

• Urokinase

• (also called thrombolytic drugs)