Primary Hemostasis

Question 1

Hemostasis

Answer 1

the cessation of bleeding at vascular injury site via the formation of a thrombus

Question 2

A thrombus consists of what two primary components?

Answer 2

1. Platelet Plug
2. Fibrin Clot

Question 3

What is Primary hemostasis?

Answer 3

Platelet Plug: Circulating platelets form a physical plug by adhering to the injury site (and each other) in order to stop the leak

Question 4

From what are platelets produced?

Answer 4

Megakaryocytes in the bone marrow

Question 5

Define Thrombocytopenia

Answer 5

having a platelet count less than 1x10⁵ /mL

Question 6

What part of platelets allows them to bind to damaged vessel walls and/or to eachother?

Answer 6

Platelets contain glyoproteins (glycosylated, integral membrane proteins) which mediate binding to collagen and von Willebrand factor

Question 7

The glycoprotein on platelets GPIb binds to what?

Answer 7

von Willebrand factor

Question 8

The glycoprotein on platelets GPIIb/IIIa binds to what?

Answer 8

• von Willebrand factor
• Fibrinogen

Question 9

What are the two types of granules (Storage vesicles) that platelets contain? What do each store?

Answer 9

1. Dense granules (Ca²⁺, ADP)
2. Alpha granules (von Willebrand factor, fibrinogen, coagulation factor V and VIII)

Question 10

Damage to endothelial lining results in the exposure of what two subendothelial molecules that are essential for the initial adhesion of platelets at the site of injury?

Answer 10

• Collagen
• von Willebrand Factor

Question 11

What are the four relevant binding sites of vWF protein?

Answer 11

• coagulation factor VIII
• GPIb
• Collagen
• GPIIb/IIIa

Question 12

Resting platelets initially adhere at damaged site via GPIb glycoproteins that bind to vWF. Is this interaction strong?

Answer 12

This interaction (GPIb-vWF-collagen) is fairly weak; platelets are tethered to subendothelia but are not firmly adhered?

Question 13

How does high shear forces create a stronger adhesion between platelets and subendothelial cells?

Answer 13

High shear forces produce a conformational change in vWF that enhances its binding to GPIb

• Therefore; increased platelet adhesion in arteries

Question 14

Upon platelet activation, undergoes a conformation change that reveals a preveioulsy hidden binding site for .

Answer 14

• GPIIb/IIIa
• vWF or fibrinogen

Question 15

What process begins Primary Aggregation of Platelets to Subendothelial cells at injury site?

Answer 15

Activated GPIIb/IIIa binds to vWF at subendothelial surface to promote strong adhesion to the vessel wall

Question 16

Activated platelets synthesis and secrete what in Secondary Activation?

Answer 16

• TXA₂
• ADP
• These two Platelet Agonists activate other resting platelets

Question 17

How do the platelet agonists (ADP, Thrombin, TXA₂ stimulate activation of resting platelets?

Answer 17

1. Each agonist binds to its specific Gq-linked receptor
2. Via Gq-mediated signaling, an increase in cytosolic Ca²⁺ occurs
3. Calcium leads to the activated on PLA₂
4. PLA₂ hydrolyzed membrane phospholipids leading to production of TXA_(1-3)

Question 18

What is the significance of GPIIb/IIIa molecules on platelets binding to fibrinogen?

Answer 18

Secondary Aggregation: One fibrinogen molecule can be bound by TWO GPIIb/IIIa molecules (from adjacent platelets) allows fibrinogen to secure platelets together

Question 19

In healthy vasculature, cirulating platelets are maintained in an INACTIVE state by endothelia in what 3 ways?

Answer 19

1. Endothelial cells secrete Nitric Oxide: inhibits platelet aggregation and promotes vasodilation
2. Endothelial cells express a membrane associated ADPase: degrades ADP that is released from activated platelets
3. Endothelial cells release PGI₂ which binds to Ga-s coupled receptor and indirectly prevents activation of phospholipase A (needed for eicosanoid synthesis)

Question 20

What is the mechanism of PGI₂ in the prevention of platelet plug formation?

Answer 20

1. Healthy Endothelia secrete PGI₂
2. PGI₂ binds to Gs-linked membrane receptor on platelet
3. Increase in cAMP and PKA
4. cAMP activates calcium pump that actively transports calcium from from the cytoplasm
5. Decrease in cytosolic Ca²⁺ prevents Ca²⁺ activation of PLA₂
6. No PLA₂ means synthesis of TXA₂ in inhibited

Question 21

What is the mechanism of action of Aspirin?

Answer 21

• COX enzyme inhibitor -> decreased TXA₂ synthesis
• Decreased platelet activation and degranulation

Question 22

What is the mechanism of action of Plavix?

Answer 22

• ADP-receptor inhibitor
• Decreased ADP-mediated secondary activation

Question 23

What is the mechanism of action of Abciximab (Reopro)

Answer 23

Inhibit GPIIb/IIIa interaction -> decreased platelet aggregation

Question 24

What is the mechanism of action of Dipyridamole?

Answer 24

• PGI₂ agonist
• Inhibits phosphodiesterase that breaks down cAMP
• (inc. cAMP → dec. cytosolic Ca_²⁺ → dec. PLA₂ activity and thrombosis)

Question 25

von-Willebrand Disease * Platelet defect? * Platelet function affected?

Answer 25

1. Defective or deficient von Willebrand factor 2. Adhesion to vWF, primary aggregation (GPIIb/IIIa); Factor VIII (half-life was prolonged by vWF)

Question 26

Thrombotic Thrombocytopenic Purpura 1. Platelet defect? 2. Platelet function affected?

Answer 26

1. Mutation of ADAMTS13 results in high levels of high molecular weight vWF 2. Exaggerated thrombosis (increased platelet plug formation) 3. Thrombocytopenia (due to abnormally high use of platelets to form microthrombi)

Question 27

Bernard-Soulier Syndrome (Giant Platelet syndrome) 1. Platelet defect 2. Platelet function affected

Answer 27

1. Defect or deficiency of **GPIb** 2. Adhesion to vWF 3. Prolonged bleeding time

Question 28

Idiopathic Thrombocytopenic Purpura 1. Platelet defect 2. Platelet function affected

Answer 28

1. Immune response against GPIb or GPIIb/IIIa 2. Platelets are destroyed by cells of the immune system 3. Severe Thrombocytopenia 4. Facilitate platelet degradation by macrophages in spleen → SPLENOMEGALY

Question 29

Glanzmann Thrombasthenia 1. Platelet Defect 2. Platelet Function affected

Answer 29

1. Defect or defiency of GPIIb/GPIIIa 2. Primary aggregation (binding to vWF) 3. Secondary aggregation (binding to fibrinogen)