Coagulation JS Jan 2013

7/28/2019 Coagulation JS Jan 2013

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Blood Clotting (Coagulation)

The process of blood clotting and then the subsequent

dissolving of the clot, following repair of the injured tissue,

is termed Haemostasis.

A problem with the coagulation system is called a

Coagulopathy.i.e.Depletion of a factor (absence)

Deficiency of a factor (decreased amount)

Dysfunction of a factor (not working)

John Santangelo


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Bone Marrow

John Santangelo


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Platelets

Small, granulated bodies that aggregate at the site of injury

Non-nucleated

Half-life of 4 days Count- 150 400 x 109/L of blood

Made from megakaryoblasts in Bone marrow


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Thrombopoiesis

Pluripotent stem cell

Committed stem cell

Megakaryoblast

Megakaryocyte

Platelets


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Megakaryocytes

Giant cells- 35-160m in diameter

Multinucleated

Forms 2000-4000 platelets

Platelets formed by pinching off ofcytoplasm

Megakaryocyte


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Thrombopoietin

Produced in kidney and liver

Cause megakaryocyte maturation

Bound to platelets- feedback


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Platelet morphology

Non-nucleated, Colorless disc, 2-4 m in diameter

Cell membrane: 6 nm in thickness

Phospholipids important in initiation of

Coagulation

Receptors for ADP, vWF, collagen, fibrinogen,

thrombin


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Functions of platelets

1.Hemostasis

2. Coagulation of blood

3. Clot retraction

4. Phagocytosis

5. Storage and transport- serotonin &

histamine


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Primary Haemostasis

Dependent on Platelets and Von Willebrand Factor (vWF)

Platelets gather and attach to vWF

vWF is needed for platelet adhesion

Platelets degranulate after attachment and release ADP and

Thromboxane which attracts more platelets

Forms a platelet plug

Requires endothelial damage to adhere


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Secondary Hemostasis

Platelet aggregation initiates secondary haemostasis through

the coagulation cascade

Coagulation cascade is initiated by the intrinsic or extrinsicpathway

The final cascade results in fibrin deposition cross-linking

platelets and clot formation


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Thrombocytopaenia:

A reduction in platelets below the Normal Reference Range (NRR)

Bone marrow depression

Hypersplenism

Viral infections

Idiopathic Thrombocytosis:

Splenectomy

Epinephrine administration

Unknown cause

Adrenalin

Platelet NRR = 150 400 x 109

/L


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Vivo:

Inside the body

Vitro:

Outside the body


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Thrombocytosis:

An increase in platelets above the Normal Reference Range (NRR)

Thrombocytopaenia:

A decrease in platelets below the Normal Reference Range (NRR)

Thromboasthenia:

Abnormal platelet function

Normal Reference Range for platelets:

150

400 x 109/L

Platelets are also called, Thrombocytes


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Epistaxis: Bleeding nose

Menorrhagia: Excessive bleeding during menstruation

Petechiae: Bleeding under the skin. (small red spots)

Purpura: Bleeding under the skin. (the small red spots join)

Petechiae


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Purpura


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Liver


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Femur


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The initial phase of the coagulation process is vascular constriction.

This limits the flow of blood to the area of injury.

Next, platelets become activated by thrombin and aggregate at

the site of injury, forming a temporary, loose platelet plug.

The protein fibrinogen is primarily responsible for stimulating

platelet clumping.

Platelets clump by binding to collagen that becomes exposedfollowing rupture of the endothelial lining of vessels.

Upon activation, platelets release the nucleotide, ADP and the

eicosanoid, TXA2 (both of which activate additional platelets),

serotonin, phospholipids, lipoproteins, and other proteinsimportant for the coagulation cascade. In addition to induced

secretion, activated platelets change their shape to

accommodate the formation of the plug.


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To insure stability of the initially loose platelet plug, a fibrin

mesh (also called the clot) forms and entraps the plug.

If the plug contains only platelets it is termed a white thrombus.

If red blood cells are present it is called a red thrombus.


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Finally, the clot must be dissolved in order for normal blood

flow to resume following tissue repair.

The dissolution of the clot occurs through the action of the

conversion ofplasminogen to plasmin.

Two pathways lead to the formation of a fibrin clot:

The intrinsic pathway

and

The extrinsic pathway.

These two pathways converge on a common pathway thatleads to clot formation.

Both pathways are complex and involve numerous different

proteins termed clotting factors.


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Hemostasis

Injury to vessel

Constriction of injured vessel (vasospasm)

Platelet adhesionPlatelet activation and aggregation

Temporary platelet plug formation

Activation of clotting factors

Fibrin network

True clot


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When blood is collected into a tube it clots.

It clots faster in a glass tube because of the rough surface of

the glass.

When collected into a plastic tube it takes much longer because

the plastic is has a smooth surface.

The plastic tubes are coated on the inside to promote clotting

When the skin is cut it provides a rough surface whichpromotes clotting as well as the cut tissue releasing tissue

factor.

To perform a coagulation test, unclotted blood is needed.

Coagulation test should be done within 4 hours of collection

The easiest way to stop blood clotting in the tube is to

remove one of the clotting factors.

Th i t l tti f t t it CALCIUM (F t IV)


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The easiest clotting factor to remove it CALCIUM. (Factor IV)

Note that we use Roman Numerals for the clotting factors.

The blood collected from a patient to perform Coagulation studies is

placed into a tube containing 3.8% Sodium Citrate.

Sodium Citrate is an anticoagulant

The ratio of Sodium Citrate to Whole Blood is 1:10

0.5mL Sodium Citrate + 4.5mL Whole BloodThe Citrate combines with the Calcium making it unavailable for

clotting.

Therefore the blood remains liquid.

In the laboratory, calcium is added to this blood and the time it takes

to form a clot in the plasma is measured.

Note that plasma is used to perform the test not whole blood or

Serum.

All th l ti f t d d i th Li


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All the coagulation factors are produced in the Liver

except the following:

VIII & vWF (Von Willebrand Factor )

Factors II VII IX X are Vitamin K dependent

The normal bacterial flora in the bowel (E Coli)

produces Vitamin K

It is also available from plant and animal sources

In the newborn, there is no normal bowel flora so a newborn

is often vitamin K deficient. Newborn babies are given vitamin

K soon after birth to prevent bleeding.

Broad spectrum antibiotics also deplete the normal E Coli

bowel flora.

N ll th bl d i li id i id th bl d l


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Normally the blood remains liquid inside the blood vessels.

There are two systems that initiate blood clotting:

The Intrinsic System and the Extrinsic System.

The Intrinsic pathway can be initiated by events that take

place within the lumen of blood vessels.

The Intrinsic pathway requires only elements (clotting factors,

Ca++, platelet surface etc.) found within, orintrinsic to thevascular system.

The Extrinsic pathway is the other route to coagulation.

It requires Tissue Factor (tissue thromboplastin), a substancewhich is "extrinsic to", or not normally circulating in the

vessel.

Tissue Factor is released when the vessel wall is ruptured.

T t f d t di l th


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Tests performed to diagnose a coagulopathy

Prothrombin Time (PT)

To measure the Extrinsic system

Will be abnormal if there are deficiencies in the following factors:

I, II, V, VII, X

Activated Partial Thrombin Time (APTT)

To measure the Intrinsic system


I, II, V, VIII, IX, X, XI, XII

Thrombin Time (TT)


I

Test for Common pathway:

Both A.P.T.T. and P.T.

There is NO single screening test for the Common Pathway

T t f d t di l th t


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Tests performed to diagnose a coagulopathy - cont

D-Dimer:

When the clot breaks down (fibrin degrading) it releases fibrin degradation

products. D-Dimer measures these breakdown products.

Platelet Aggregation test:

The platelet aggregation test aids in the evaluation of bleeding disorders by

measuring the rate and degree to which platelets form a clump (aggregate) after

the addition of a chemical that stimulates clumping (aggregation).Several different substances called agonists are used in the test.

These agonists include adenosine diphosphate, (ADP) epinephrine, thrombin,

collagen, and ristocetin.

An agonist is a chemical that binds to a receptor of a cell and triggers a

response by that cell.


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Old Tests

Bleeding timeTests vascular integrity and platelet function

Incision on volar aspect of the forearm 1mm deep

and 1 cm long

BP cuff inflated to 40 mmHgNormal < 8 minutes

Borderline 8-10 minutes

Abnormal 10 + minutes

Affected by ASA (acetylsalicylic acid, Aspirin ) (permanent)and NSAIDs


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Thromboasthenia

Platelet function disorder

Tests:

Old Tests:

Bleeding & Clotting time

New Test:

PFA 100

Plate Function Analysis 100


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Normal Reference Range:

The Normal Reference Range for a particular test or measurement is usually

defined as the prediction interval between which 95% of values of the healthy

population fall into, whatever the distribution of these values. In case of normal

distribution, it can alternatively be defined as the interval limited by 2 standard

deviations from either side of the mean.

It is sometimes referred as "reference interval", normal range or normal values(and sometimes "usual" range/values). All these terms should be discouraged as

not everyone outside the interval is abnormal, and people who have a particular

condition may still fall within this interval.

Therapeutic range:

The range of concentrations at which a drug or other therapeutic agent is effective

with minimal toxicity to most patients.

A minimum of 100 patients are selected to establish a


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Total = 95.4%

A minimum of 100 patients are selected to establish a

Normal Reference Range

Within 2 Standard Deviations


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Coagulation JS Jan 2013

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