LESSON 2 - INTRODUCTION TO PLATELETS

Megakaryopoiesis

The process of platelet production in the bone marrow.

Megakaryopoiesis

It begins with a multipotent hematopoietic stem cell, which differentiates into a megakaryocyte lineage.

Hematopoietic Stem Cell (HSC)

Common progenitor for all blood cells.

Megakaryoblast

The earliest recognizable precursor in platelet production, it is large that is characterized by a high nuclear:cytoplasmic ratio.

Promegakaryocyte

Begins to develop granules, and with apparent lobulation

Megakaryocyte

A large cell in the bone marrow with multilobed nuclei that undergoes endomitosis.

Endomitosis

There is increased DNA content without cell division

Platelets

Cytoplasmic fragments of the mature megakaryocytes were noted as not being full cells.

Megakaryoblast

Earliest recognizable stage of maturation

Megakaryoblast

Originates from the Hematopoietic Stem Cell

Megarkoblast

Undergoes multiple mitotic division without cytoplasmic division.

Megakaryoblast

Normally found only in the bone marrow in their 3rd or 4th stage of differentiation

Megakaryoblast

The first recognizazble stage in megakaryocytic development

Megakaryoblast

It is large, round cell with high nuclear:cytoplasmic ratio and has chromatin.

Promegakaryocyte

Has blunt protrusions

Promegakaryocyte

This cell is immature but capable of protein synthesis

Promegakaryocyte

Shows a more developed network of membrane within cytoplasm which forms by invagination of the plasma membrane

Promegakaryocyte

Cytoplasm is rich in polyribosomes

Megakaryocyte

Cytoplasm is devoid of specific granules other than polyribosomes

Megakaryocyte

The stage that does not ordinarily produce platelets

Megakaryocyte

Contains numerous small uniformly distributed granules with a reddish-blue hue

Metamegakaryocyte

A very large cell and causes decrease in its nuclear-cytoplasmic ratio

Metamegakaryocyte

The stage that does not ordinarily produce plateletsbut is crucial for the maturation of megakaryocytes into platelets.

1000-4000 platelets

Around how much can each megakaryocyte or metamegakaryocyte shed during the process of platelet production.

Megakaryoblast

Cytoplasmic Granules: Not present

Cytoplasmic Tags: Present

Nuclear Features: Large single nucleus with fine chromatin and prominent nucleoli.

Visibility of Thrombocytes: None

Promegakaryocyte

Cytoplasmic Granules: Few present

Cytoplasmic Tags: Present

Nuclear Features: Double Nuclei

Visibility of Thrombocytes: None

Megakaryocyte

Cytoplasmic Granules: Numerous

Cytoplasmic Tags: Usually absent

Nuclear Features: Two or more nuclei

Visibility of Thrombocytes: None

Metamegakaryocyte

Cytoplasmic Granules: Aggregated

Cytoplasmic Tags: Absent

Nuclear Features: Four or more nuclei

Visibility of Thrombocytes: YES

Thrombopoietin (TPO)

It is the primary regulator of platelet production and the hormone that stimulates the production and megakaryocyte maturation.

Thrombopoietin (TPO)

Mainly produced by the liver, but may also be produced by the kidney.

Thrombopoietin (TPO)

ROLES: megakaryocyte proliferation, maturation, and platelet release

Thrombopoietin (TPO)

Inversely related to platelet count, as platelet levels rise, TPO levels decrease to maintain homeostasis.

Interleukin (IL)

Cytokines that enhance or increase megakaryocyte size, maturation, and ploidy during platelet production.

Interleukin (IL)

Increases megakaryocyte size by promoting cytoplasmic expansion, preparing the cell for platelet production.

White blood cells

Where do cytokines come from?

Interleukin 3

supports early hematopoietic stem cell differentiation in the megakaryocyte

Interleukin 6

stimulates the liver to produce more TPO

Interleukin 6 and 11

Promotes endomitosis; enhance megakaryocyte maturation and platelet production, particularly during inflammation or stress

Granulocyte-macrophage Colony Stimulating Factor (GM-CSF)

Stimulates megakaryocyte size, maturation, and ploidy.

Vasoconstriction

The immediate response of blood vessels to constrict and reduce blood flow during injury.

To reduce blood flow

After your blood vessel is injured, your smooth muscle in the blood vessel will constrict. Why?

Serotonin and Thromboxane A2

are released by activated platelets to promote vasoconstriction and platelet aggregation.

Fibrinolysis

Removes the clot once the vessel is repaired.

Fibrinolysis

Plasminogen is now activated to plasmin which breaks down the formed clot.

Fibrinolysis

Plasmin degrades fibrin, dissolving the clot

Platelet Activation

The process where platelets respond to vessel injury by changing shape and sticking to the damage site, forming a temporary platelet plug.

Coagulation

As platelet activations seals the wound quickly, this forms the permanent clot.

Platelet Adhesion

The platelets will go to the injured site in order to seal the area.

Platelet Aggregation

The platelet will stick together with other platelets, using fibrinogen as a bridge.

Events during Platelet Activation and Platelet Adhesion

When there is vessel injury or cell damage, the underlying blood vessel wall is exposed, triggering platelets to activate. They change shape and adhere to the damaged site and exposed collagen, forming a temporary platelet plug.

Glycoprotein IIb/IIIa (GP IIb/IIIa) and Von Willebrand Factor (vWF)

Receptors that are released during platelet adhesionand aggregation, facilitating the binding of platelets to each other and to the damaged vessel wall.

Nervous System Response

The pain from the injury will signal the nervous system, which activates your sympathetic nerve, causing the blood vessel to constrict.

Vessel Vascular Response

The injured blood vessel will release a signal that would cause your smooth muscle in the vessel to constrict or contract to further reduce blood flow.

Coagulation Cascade

A series of events that lead platelets to aggregate and form stable clots.

Fibrinolysis

The process that breaks down clots once the vessel is repaired.

Collagen exposure

Triggers the intrinsic pathway of coagulation during vessel injury.

Collagen exposure

Activates thrombin (Factor IIa)

Common Pathway

Thrombin converts fibrinogen to fibrin, and fibrin mesh stabilizes the platelet plug.

Tissue Thromboplastin Release

Triggers the extrinsic pathway of coagulation, leading to rapid clot formation.

Spicules or Pseudopods

What will platelets produce once they are activated?

Pseudopods Transformation

Could form a stronger platelet plug because the platelets can now help each other.

Roles of Hemostasis

Adhere to injured vessel

Aggregate at the site of injury

Promote coagulation on their phospholipid surface

Release biochemicals important in hemostasis

Last act of platelets within the platelet-fibrin clot is contraction of the clot

Retraction Process

Involves stabilization of platelet & platelet fibrin attachment. The pulling forces are provided by contractile platelet elements.

Retraction

Participate in vascular constructive response to injury.

Stabilization of fibrin clot meshwork.

Debulking the clot to re-establish blood flow.

Peripheral Zone

Outermost layer of the platelet, essential for: adhesion, activation, and clot formation

Peripheral Zone

Consists of the surface coat or glycocalyx, plasma membrane, and submembrane area

Glycocalyx / Surface Coat

A very sticky outer layer that helps the platelets in binding to the injured vessel and to clotting factors and other platelets.

Glycocalyx / Surface Coat

It also plays a role in adhesion and aggregation as it contains glycoproteins - to be able to stick to injured vessels

Ia, Ib, IIb, III, IV, and V

Glycoproteins present in the glycocalyx/surface coat

Ia, Ib, IIb, III, IV, and V

plays important roles in platelet adhesion and aggregation, this glycoproteins act like anchors that allow platelets to stick to the vessel wall, other platelets and to clotting factors

Site for Adhesion

What role does the platelet surface play in coagulation?

Prothrombinase complex

A complex that converts prothrombin to thrombin during coagulation.

Va1, Xa, and Ca

Factors used from prothrombinase complexto facilitate the conversion of prothrombin to thrombin, essential in the coagulation cascade.

Va1

acts as a cofactor that enhances the reaction

Xa

activates the enzyme that will catalyze the conversion of prothrombin to thrombin

Calcium

help in the proper binding of clotting factors to the platelet surface

Plasma Membrane

a receptor-rich layer that detects injury signals and allows platelets to change their shape

Plasma Membrane

Outermost physical boundary of the platelet acts like a barrier that protects internal platelet components.

Plasma Membrane

Control center that will regulate what will be able to enter and exit the platelet.

Submembrane Area

Provides structural support and enables the shape change during activation

Sol-Gel Zone/Soft Zone

Underlies the submembrane filaments - constitute the matrix or muscle & skeletal portion of the platelet

Sol-Gel Zone/Soft Zone

Consists or circumferential microtubule system and randomly arranged microfilaments that form an intraplatelet matrix that support the platelet discoid shape

Sol-Gel Zone/Soft Zone

Serves as a stable gel component to regulate the arrangement of the internal organelles and microtubular system in the platelets

Sol-Gel Zone/Soft Zone

Contain actin and myosin, which interact to formActomyosin which is important for clot retraction.

Organelle Zone

constitute the major portion of the platelet cytoplasm which include electron dense granules, alpha granules, peroxisomes, lysosomes, and mitochondria.

Types of Granules

Dense/Delta Granules

Alpha/L Granules

Lysosomes

Dense/Delta Granules

ADP, ATP, serotonin, calcium & magnesium

Nucleotide ADP

considered the most significant component secreted from dense granules after platelet stimulation because it initiates platelet aggregation

Alpha/ L Granules

Factor V, Fibrinogen, Von Willebrand Factor, Thrombospondin, Platelet Derived Growth Factor (PDGF)

Lysosomes

Hydrolytic enzymes active at low pH and help break down unwanted materials.

Canicular System

Serve as delivery routes for substance ingested by the platelet and route of extrusion of substances released from the stimulated platelet.

Dense Tubular System

important role in influencing the microtubules supporting the discoid platelet shape; site for prostaglandin synthesis.

Thromboxane A2

A potent vasoconstrictor that promotes platelet aggregation.

Aspirin

Inhibits cyclooxygenase, preventing formation of Thromboxane A2 and compromising platelet function.

Platelet Life Span

Approximately 5-10 days; younger platelets are more effective in clotting than older ones.

Young a d Old Platelets

Platelets are divided into two

Young Platelet

Hemostatically more effective in clotting

Old platelets

Hemostatically less effective
30% of the total circulating platelet population are normally sequestered in the spleen.

This platelet pool exchanges freely with the circulation

Platelet Adhesion

is mediated by glycoprotein GP1b and will interact with Von Willebrand factor to anchor the platelet to the injury site

Platelet Adhesion

The process by which platelets attach to the damaged site of injured blood vessels.