Platelet Function and Hemostasis

Functions of Platelets

Introduction

• The primary function of platelets is to form a primary plug at the site of an injury.

• This plug, formed rapidly, provides temporary control of bleeding.

Von Willebrand Factor (vWF)

• vWF is a large, complex, multimeric protein composed of several subunits.

• Synthesis:

  • Endothelial cells

  • Megakaryocytes

• Storage:

  • Endothelial cells

  • Platelet α granules

• Functions:

  • Platelet adhesion to the vessel wall.

  • Carries factor VIII.

Platelet Function

• Platelets form the primary plug at the injured vessel through a series of steps:

  • Platelet adhesion

  • Platelet activation

  • Platelet release reaction

  • Platelet aggregation

  • Platelet procoagulant activity

1) Platelet Adhesion

• Platelets interact with the injured vessel.

• Following blood vessel injury, platelets adhere to exposed subendothelial tissues.

• Mechanisms:

  • The plt GPIa site allows direct adhesion to collagen.

  • The plt GPIb site binds vWF, which binds to subendothelial microfibrils.

  • The GP IIb/IIIa receptor complex forms a secondary binding site with vWF, further enhancing adhesion.

2) Platelet Activation

• Following adhesion, platelets activate and become more spherical (shape change).

  • They extrude long pseudopods, enhancing interaction in platelet adhesion and aggregation.

  • Platelet GP sites (GPIIb/IIIa) are activated.

  • Granule secretion is enhanced (platelet release reaction).

• The protein actin causes platelet contraction.

3) Platelet Release Reaction

• It is the secretion of platelet granules contents like ADP, Calcium etc.

• Platelets activate the synthesis of thromboxane A2 (TXA2).

• Released ADP & TXA2 increases platelet aggregation at the injury site.

• This process results in the formation of a platelet mass large enough to plug the injured site.

• Note: Aspirin is an antiplatelet drug that inhibits TXA2 synthesis, thus reducing platelet aggregation.

4) Platelet Aggregation

• Activated platelets also activate the GPIIb/IIIa site, which promotes binding between platelets and fibrinogen, leading to platelet aggregation.

• Platelet aggregation is the cross-linking of platelets with fibrinogen bridges.

• This process is Calcium ($Ca^{+2}$)-dependent.

• A potent aggregator is ADP.

5) Platelet Procoagulant Activity

• Platelet aggregation and release reaction accelerate the coagulation process by:

  • Providing abundant exposed membrane phospholipid.

  • Providing many coagulation factors.

• The coagulation reactions are Calcium ($Ca^{+2}$)-dependent.

Platelet Plug Formation (Summary)

• In response to blood vessel (endothelial) injury, platelets adhere and are activated at the injury site, squeezing their granule contents outside of the platelets then aggregate to each other to form a primary unstable plug.

  1. Adherence:

     • Collagen (subendothelial) ↔ GP Ia (platelet)

     • Microfibrils (subendothelial) ↔ vWF ↔ GP Ib (platelet)

  2. Further Adherence:

     • Microfibrils (subendothelial) ↔ vWF ↔ GP IIb/IIIa (platelet)

  3. Aggregation:

     • GP IIb/IIIa (of one platelet) ↔ fibrinogen ↔ GP IIb/IIIa (of other platelet)

Clinical Notes

• vWF deficiency → von Willebrand disease

• GPIb deficiency → Bernard-Soulier Syndrome

• GP11b/111a deficiency → Glanzmann thrombasthenia

Tests of Platelets

1. Platelet Count ($(150 – 400) × 10^9/L$)

• Manual platelet counts are rarely performed.

• Most CBC analyzers count Platelets.

• Interpretation:

  1. Low platelet count: Thrombocytopenia

     • Abnormal bleeding occurs when platelets are < $60 × 10^9/L$

     • Main causes: chemotherapy, radiation, anti-platelet antibodies (Abs), Disseminated Intravascular Coagulation (DIC), etc.

  2. High platelet count: Thrombocytosis

     • Mainly found in myeloproliferative disorders.

2. Platelet Aggregation

• The ability of platelets to aggregate can be measured by adding substances such as ADP to a platelet concentrate and observing the rate at which they aggregate.

3. Bleeding Time (BT)

• An incision (cut) is made in the skin while a blood pressure cuff maintains a constant venous pressure of 40 mm Hg.

• The size & depth of the cut are standardized at 1mm deep & 6mm long.

• The time taken for bleeding to stop is the bleeding time.

• Reference range: 2.5 - 9.5 min

• Interpretation: Prolonged bleeding times occur when:

  1. vessels are abnormal → vascular disorders

  2. abnormal platelet function → platelet disorders

Vascular System (Blood Vessels)

• The blood vessels stop bleeding by:

  • Contraction of the injured vessel (vasoconstriction).

  • Slowing blood flow around damaged vessels.

  • Activation of platelets and the coagulation system.

Mechanisms of Vascular System

• By producing substances from injured blood vessels:

  • Synthesis of von Willebrand factor (vWF) → promotes platelet adhesion & carrier for FVIII

  • Release ADP, adrenaline & serotonin → Platelet aggregation

  • Release of Tissue factor (TF) → promoters for the coagulation pathway

• By producing substances from healthy blood vessels:

  • Synthesis of prostacyclin & ADPase → inhibits platelet aggregation & promotes vasodilation → (platelet inhibitors)

  • Release of Tissue plasminogen activator (t-PA) → Fibrinolysis

  • Contain thrombin receptor site (thrombomodulin) → Fibrinolysis

  • Secrete heparin & antithrombin III (ATIII) → Natural Anticoagulants

Tests for Blood Vessel Function

• Some disorders of hemostasis are due to a defect in the blood vessels (some vascular disorders lead to bleeding tendency).

• The only laboratory test useful to detect vascular disorders is the bleeding time test (mentioned earlier in the platelets function tests).

Definitions

• COAGULATION: Process of converting fibrinogen to fibrin (clotting).

• AGGREGATION: The joining together of platelets by a natural tendency to stick to each other.

• ADHESION: The sticking of platelets to another surface or tissue.

• COAGULANT: A substance that encourages (promotes) coagulation.

• FACTOR: A substance in plasma that takes part in coagulation.

• INHIBITOR: A substance that discourages or neutralizes a factor involved in coagulation.

• ANTICOAGULANT: A substance that prevents the formation of a clot.

• PLASMA: The blood fluid before a clot forms.

• SERUM: The blood fluid after a clot forms.

Introduction

• The primary function of platelets is to form a primary plug at the site of an injury.

• This plug, formed rapidly, provides temporary control of bleeding.

Platelet Function

• Platelets form the primary plug at the injured vessel through a series of steps:-

  • Platelet adhesion

  • Platelet activation

  • Platelet release reaction

  • Platelet aggregation

  • Platelet procoagulant activity

1) Platelet Adhesion

• Platelets interact with the injured vessel.

• Following blood vessel injury, platelets adhere to exposed subendothelial tissues.

• Mechanisms:

  • The plt GPIa site allows direct adhesion to collagen.

  • The plt GPIb site binds vWF, which binds to subendothelial microfibrils.

  • The GP IIb/IIIa receptor complex forms a secondary binding site with vWF, further enhancing adhesion.

4) Platelet Aggregation

• Activated platelets also activate the GPIIb/IIIa site, which promotes binding between platelets and fibrinogen, leading to platelet aggregation.

• Platelet aggregation is the cross-linking of platelets with fibrinogen bridges.

• This process is Calcium ($Ca^{+2}$)-dependent.

• A potent aggregator is ADP.

Vascular System (Blood Vessels)

• The blood vessels stop bleeding by:-

  • Contraction of the injured vessel (vasoconstriction).

  • Slowing blood flow around damaged vessels.

  • Activation of platelets and the coagulation system.

Mechanisms of Vascular System

• By producing substances from injured blood vessels:

  • Synthesis of von Willebrand factor (vWF) → promotes platelet adhesion & carrier for FVIII

  • Release ADP, adrenaline & serotonin → Platelet aggregation

  • Release of Tissue factor (TF) → promoters for the coagulation pathway

• By producing substances from healthy blood vessels:

  • Synthesis of prostacyclin & ADPase → inhibits platelet aggregation & promotes vasodilation → (platelet inhibitors)

  • Release of Tissue plasminogen activator (

Functions of Platelets

Introduction

• The primary function of platelets is to form a primary plug at the site of an injury.

• This plug, formed rapidly, provides temporary control of bleeding.

Platelet Function

• Platelets form the primary plug at the injured vessel through a series of steps:

  • Platelet adhesion

  • Platelet activation

  • Platelet release reaction

  • Platelet aggregation

  • Platelet procoagulant activity

1) Platelet Adhesion

• Platelets interact with the injured vessel.

• Following blood vessel injury, platelets adhere to exposed subendothelial tissues.

• Mechanisms:

  • The plt GPIa site allows direct adhesion to collagen.

  • The plt GPIb site binds vWF, which binds to subendothelial microfibrils.

  • The GP IIb/IIIa receptor complex forms a secondary binding site with vWF, further enhancing adhesion.

4) Platelet Aggregation

• Activated platelets also activate the GPIIb/IIIa site, which promotes binding between platelets and fibrinogen, leading to platelet aggregation.

• Platelet aggregation is the cross-linking of platelets with fibrinogen bridges.

• This process is Calcium ($Ca^{+2}$)-dependent.

• A potent aggregator is ADP.

Vascular System (Blood Vessels)

The blood vessels stop bleeding by:

Contraction of the injured vessel (vasoconstriction).

Slowing blood flow around damaged vessels.

Activation of platelets and the coagulation system.

Mechanisms of Vascular System

By producing substances from injured blood vessels:

Synthesis of von Willebrand factor (vWF) → promotes platelet adhesion & carrier for FVIII

Release ADP, adrenaline & serotonin → Platelet aggregation

Release of Tissue factor (TF) → promoters for the coagulation pathway

By producing substances from healthy blood vessels:

Synthesis of prostacyclin & ADPase → inhibits platelet aggregation & promotes vasodilation → (platelet inhibitors)

Release of Tissue plasminogen activator (t-PA) → Fibrinolysis

Contain thrombin receptor site (thrombomodulin) → Fibrinolysis

Secrete heparin & antithrombin III (ATIII) → Natural Anticoagulants

Vascular System (Blood Vessels)

The blood vessels stop bleeding by:

Contraction of the injured vessel (vasoconstriction).

Slowing blood flow around damaged vessels.

Activation of platelets and the coagulation system.

Mechanisms of Vascular System

By producing substances from injured blood vessels:

Synthesis of von Willebrand factor (vWF) → promotes platelet adhesion & carrier for FVIII

Release ADP, adrenaline & serotonin → Platelet aggregation

Release of Tissue factor (TF) → promoters for the coagulation pathway

By producing substances from healthy blood vessels:

Synthesis of prostacyclin & ADPase → inhibits platelet aggregation & promotes vasodilation → (platelet inhibitors)

Release of Tissue plasminogen activator (t-PA) → Fibrinolysis

Contain thrombin receptor site (thrombomodulin) → Fibrinolysis

Secrete heparin & antithrombin III (ATIII) → Natural Anticoagulants

Vascular System (Blood Vessels)

The blood vessels stop bleeding by:

Contraction of the injured vessel (vasoconstriction).

Slowing blood flow around damaged vessels.

Activation of platelets and the coagulation system.

Mechanisms of Vascular System

By producing substances from injured blood vessels:

Synthesis of von Willebrand factor (vWF) → promotes platelet adhesion & carrier for FVIII

Release ADP, adrenaline & serotonin → Platelet aggregation

Release of Tissue factor (TF) → promoters for the coagulation pathway

By producing substances from healthy blood vessels:

Synthesis of prostacyclin & ADPase → inhibits platelet aggregation & promotes vasodilation → (platelet inhibitors)

Release of Tissue plasminogen activator (t-PA) → Fibrinolysis

Contain thrombin receptor site (thrombomodulin) → Fibrinolysis

Secrete heparin & antithrombin III (ATIII) → Natural Anticoagulants

Vascular System (Blood Vessels)

The blood vessels stop bleeding by:

Contraction of the injured vessel (vasoconstriction).

Slowing blood flow around damaged vessels.

Activation of platelets and the coagulation system.

Mechanisms of Vascular System

By producing substances from injured blood vessels:

Synthesis of von Willebrand factor (vWF) → promotes platelet adhesion & carrier for FVIII

Release ADP, adrenaline & serotonin → Platelet aggregation

Release of Tissue factor (TF) → promoters for the coagulation pathway

By producing substances from healthy blood vessels:

Synthesis of prostacyclin & ADPase → inhibits platelet aggregation & promotes vasodilation → (platelet inhibitors)

Release of Tissue plasminogen activator (t-PA) → Fibrinolysis

Contain thrombin receptor site (thrombomodulin) → Fibrinolysis

Secrete heparin & antithrombin III (ATIII) → Natural Anticoagulants