Hemostasis

Question 1

Define the terms ‘hemostasis’ and ‘thrombosis.’

• steps of primary hemostais

Answer 1

hemostasis: stopping flow of blood

thrombosis: formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system

Steps of Primary Hemostasis

1. vasoconstriction
2. platelet adhesion
3. platelet activation
4. platelet aggregation

Question 2

Describe the general kinetics of platelet formation and turnover.

Answer 2

Enzyme Kinetics

• Increase in [S] leads to increase in enzyme velocity which increases product
• Prothrombin substrate levels are in the concentration sensitive range of Michaelis graph
• Number of productive complexes correlates with amount of thrombin generated

Question 3

Outline the sequential mechanisms of normal hemostasis.

Answer 3

Vasoconstriction: (didn’t talk about)

Adhesion: Platelets have receptors for collagen and von Willebrand factor and will attach to the vWF of exposed endothelium; When receptors on platelets interact with collagen/vWF they undergo a conformational change and induce an outward-in signal to leads into an inward-out signal that activated fibrinogen receptors (GPIb)

Activation: Thrombin directly activates platelets via proteolytic cleavage of the protease-activated receptor.; Thrombin also stimulates platelet granule release of adenosine diphosphate (ADP). Binding of ADP to its receptor induces GpIIb/IIIa expression at platelet surface.

Aggregation: process by which fibrinogen forms bridges between GPIIb/IIIa receptors on adjacent platelets; Acidic phospholipids (-) facing outward from platelets which interact with (+) calcium that then interacts with (-) y-carboxyglutamic acid on vitamin k dependent factor

Question 4

Compare the anticoagulant and procoagulant features of endothelium.

Answer 4

Endothelium mechanisms for inhibiting coagulation

• Prostacycin and ADP-ASE: inhibit PLT recruitment and activation
• Heparin sulfate proteoglycan: cofactor for antithrombin coagulation inhibitor
• Thrombomodulin and protein C receptor: activated protein C cleaves coagulation factors

Question 5

Give an overview of the coagulation cascade, including its proteolytic targets

• cascade outline
• vitamin k dependent factors

Answer 5

• cascade outline: see picture
• vit. k dependent factors: VII, IX, X, II, C, S
• helper factors: V, VIII

Question 6

Describe the pathways of blood coagulation, and how these are tested in the clinical hemostasis laboratory to identify coagulation disorders. (PT, PTT)

Answer 6

factors that affect PT: VII, X, V, II (extrinsic)

factors that affect PTT: XI, IX, VIII, common pathway factors, XII; more sensitive to heparin than PT (intrinsic)

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Question 7

Describe the importance of lipid-soluble vitamin K in platelet formation.

Answer 7

• Zymogens modified by vitamin K dependent processes in liver: VII, IX, X, prothrombin
• Carboxyl group added to zymogens make them more negative; helps binding with calcium
• γ-carboxyglutamate modifications target clotting factors to platelet membranes (gives negative charge that interacts with positive calcium that are interacting with negative plateletes)

Question 8

ADAMTS13 enzyme

Answer 8

enzyme that cleaves giant clumps of vWf factor; keeps platelets sticking to just the area that they are needed

Question 9

“Describe the general sequence of events leading to hemostasis at a site of vascular injury, and explain the critical role platelets play in hemostasis and tissue repair.”

• things that activate clotting

Answer 9

• Extrinsic Pathway: Tissue factor from ruptured vessel; tisse factor comes from adventitia layer of blood vessel wall (positive charge; outermost layer of blood vessel)
• Intrinsic Pathway: exposure to polyphosphate (negative charged substance)