physiology and pathology of clotting

What is blood composed of?

Plasma
Erythrocytes
Leukocytes
Platelets

Blood plasma

Watery solution of electrolytes, plasma proteins, carbohydrates and lipids

Erythrocytes

Red blood cells

Leukocytes

White blood cells

Platelets

Nucleus free fragments that are important in clotting

Haemostasis

Prevention of haemorrhage

What is a blood clot?

A semi-solid mass that consists of erythrocytes, leukocytes, serum and a mesh of fibrin

Fibrin

Protein that forms the basis of a blood clot

List 4 ways haemostasis can be achieved?

Vasoconstriction
Increased tissue pressure
Platelet plug
Conglutination

Vasoconstriction

Narrowing of blood vessels

Function of thromboxane

Vasoconstriction and platelet aggregation

Thrombin

An enzyme in blood plasma that causes the clotting of blood by converting fibrinogen to fibrin.

Endothelin-1

Vasoconstrictor

Serotonin role in haemostasis

Vasoconstriction

Transmural pressure

Pressure difference exerted on the two sides of blood vessel

How does increased tissue pressure aid in haemostasis?

Decreases transmural pressure

Platelet plug

Accumulation and adhesion of platelets at the site of blood vessel injury

Conglutination

Clot formation
Semi solid mass of platelets and fibrin mesh with trapped erythrocytes, leukocytes and serum

How do endothelial cells maintain normal blood fluidity?

Paracrine factors
Anticoagulant factors

Anticoagulant factors

Protein C
Protein S
Antithrombin

Antithrombin

(from liver) Deactivates thrombin before it can act on fibrinogen

Thrombus

Intravascular blood clot

Intravascular

Within the blood vessel

Arterial thrombosis

Blood clot in artery

DVT risk factors

Venous stasis, vascular injury and hypercoagulability

Venous stasis

Condition of slow blood flow in the veins

Hypercoagulability

Increased ability of the blood to coagulate

DVT

Deep vein thrombosis
Blood clot develops within a deep vein in the body

Atherosclerotic plaque

The cholesterol-rich material that is deposited in the arteries of individuals with atherosclerosis. It consists of cholesterol, smooth muscle cells, fibrous tissue, and eventually calcium.

Atherosclerosis

Condition in which fatty deposits called plaque build up on the inner walls of the arteries

Arterial thrombus

Following erosion or rupture of atherosclerotic plaque, it travels elsewhere and lodges in another artery

What is blood plasma?

Watery solution of electrolytes, plasma proteins, carbohydrates and lipids

Albumin function

Protein in blood
Neutralises free radicals
Binds and transports substances like hormones
Osmotic regulation - retention of water in blood vessels

Fibrinogen

Plasma protein that is converted to fibrin in the clotting process

Globulins

Serum proteins

Hematocrit

Percentage of blood volume occupied by red blood cells

Shape of RBCs

Non-nucleated biconcave discs
Maximises SA:V

How is the shape of RBCs maintained?

By cytoskeleton anchored to the plasma membrane by glycophorin

Glycophorin

A membrane protein located on the surface of erythrocytes that anchors the cytoskeleton to the membrane

Band 3 anion exchanger

Exchanges chloride ions for bicarbonate ions

Function of erythrocytes

Oxygen transport from lungs to systemic system
Carbon dioxide transport from tissue to lungs
Buffering of acid/bases

Granulocytes

Neutrophils, eosinophils, basophils

Function of neutrophils

Phagocytose bacteria

Function of eosinophils

Combats parasites and viruses

Function of basophils

Releases interleukin 4, histamine, heparin and peroxidase

Interleukin 4

Assists in differentiation of helper T cells

Heparin

Anticoagulant

Peroxidase

An enzyme that destroys hydrogen peroxide

Non-granulocytes

Lymphocytes and monocytes

Monocytes

Macrophages and dendritic cells

Dendritic cells

Antigen-presenting cells in the skin

Platelets

Bud off megakaryocytes in the bone marrow

Megakaryocytes

Large cells that develop into platelets

Thrombopoetin

Stimulates platelet production

TPO

Thrombopoietin

Interleukin 3

Supports growth and differentiation of bone marrow stem cells

Where is TPO produced?

Liver

How are platelets released into the blood?

Blood vessels are sinusoidal
Megakaryocytes can seep through and platelets bud off and are released into the blood

Negative feedback involved in platelet formation

Receptors for TPO on platelets
Lots of plateleys \= lots of TPO receptors
Megakaryocytes not generated
Fewer platelets produced

How many platelets per microlitre of blood?

150000-450000

Structure of platelets

Nucleus free fragments
Surrounded by microtubules
Contains mitochondria, lyosomes, peroxisomes, alpha granules and dense core granules
External coat is rich in TPO receptors

Function of peroxisomes in platelets

Contains peroxidase that breaks H2O2 down

Function of alpha granules in platelets

Contain coagulation factors, fibrinogen and clotting factor 5 and Von Willebrand factor

Clotting factor 5

Proaccelerin

Von Willebrand factor

Helps platelets stick together and adhere to the walls of blood vessels at the site of a wound

Function of dense core granules in platelets

Contains ATP, ADP, serotonin and calcium ions

Function of serotonin in platelets

Released to recruit other platelets

Describe the inner skeleton structure of a platelet

Circumferential band of tubulin microtubules
Maintains resting platelet shape and reorganises platelet shapes when activated

How does hematocrit affect blood flow?

Blood flow decreases with increasing hematocrit

Blood flow equation

Q \= Delta P/R

Q \= DeltaP/R

Blood flow \= change in pressure / resistance

What is blood viscosity dependent on?

Hematocrit
Fibrinogen plasma concentration
Vessel radius
Linear velocity
Temperature

Blood viscosity

Thickness of blood

What happens to the viscosity as hematocrit increases?

Viscosity increases

At low hematocrit why does viscosity increase?

Increased levels of RBCs

At high hematocrit why does viscosity increase?

Because of cell deformation

How does temperature affect blood viscosity?

Increases in temperature decreases blood viscosity

Parabolic profile of laminar flow

Velocity of the layers of blood flow within the vessel vary, with blood in the center moving faster than blood in outer layers

Where do RBCs move faster?

In the centre of the arteriole compared to the periphery

How does viscosity affect the parabolic profile of flow?

The lower the viscosity the sharper the point

Tank treading

In small capilarries, RBCs roll around
The plasma between 2 adjacent rolling RBCs spins

How does the size of vessels affect RBCs and the viscosity?

Vessels smaller that RBCs deform the cells
Viscosity falls

Axial accumulation of RBCs

Accumulation in the centre of the blood vessel

Arterial cushion function

Prevents skimming in branch vessels

Turbulent blood flow

Type of blood flow resulting in audible sound
At high flow rate blood flow is no longer laminar and becomes turbulent
Pointed parabolic profile is blunted

When does turbulent flow occur?

Radius is large
Velocity is high
Local stenosis

Clinical sign of local stenosis

Blood flow can be heard as murmurs
Suggests turbulent blood flow

Local stenosis

Narrowing of blood vessels
E.g. atherosclerosis

How is haemorrhage prevented?

Vasoconstriction
Increased tissue pressure
Platelet plug
Clot formation

What are vasoconstrictors produced by?

Platelets

Thromboxane A

Triggers endothelin-1 release

Serotonin

Vasoconstrictor

Platelet plug formation

Platelet deposition and adhesion
Platelet activation
Platelet aggregation

Clot

Semisolif mass of platelets and fibrin mesh with trapped RBCs, WBCs and serum

How are platelets adhered to the injured epithelium?

Platelets bind to the Von Willebrand factor
The von Willebrand factor has a receptor that binds to a collagen binding site which binds it to the epithelium

What is the release of the von Willebrand factor triggered by?

High shear forces
Cytokines
Hypoxia

What does breached epithelium expose?

Collagen
Fibronectin
Laminin

What is the ligand that binds to platelets?

von Willebrand factor

What does the von Willebrand factor binding to platelets do?

Conformational changes in receptors
Intracellular signalling cascade initiated
Exocytosis of dense core granules and alpha granules
Cytoskeletal changes

3 stages of platelet plug formation

Adhesion, activation, aggregation