blood disorders

Question 1

keeping blood fluid, with the ability to coagulate when necessary is essential. What is required for this process?

Answer 1

a balance between coagulants and anticoagulants

Question 2

what is an anticoagulant? what is it needed for? what does it involve?

Answer 2

• molecule that prevents/reduces clot formation
• needed for thrombosis
• anticoagulant factors, fibrinolytic factors and healed endothelium

Question 3

what is a coagulant? what does it involve?

Answer 3

• molecule that promotes wound healing/the prevention of blood loss
• endothelial damage, platelet activation, coagulation activation

Question 4

what are two key elements of homeostasis?

Answer 4

(1) blood

(2) vascular endothelium

Question 5

what is blood comprised of? (2)

Answer 5

(1) plasma = liquid component that plays a role in the transport of proteins, hormones, electrolytes, etc.
(2) cellular components = platelets, erythrocytes, leukocytes

Question 6

when there is no injury to vasculature platelets are in what state?

Answer 6

the quiescent state

Question 7

what is vascular endothelium?

Answer 7

-a mono-layer of endothelial cells that (under resting conditions) produce factors tht prevent inapropriate initiation of homeostasis

Question 8

what separates blood and procoagulant factors found in the subendothelial layer? why is this important for homeostasis?

Answer 8

• vascular endothelium
• when there’s an injury to the vascular endothelium, blood is exposed to these procoagulant factors and platelet plug formation begins

Question 9

what are the three stages of homeostasis? explain what happens (generally) in each.

Answer 9

1° homeostasis = vasoconstriction and formation of the platelet plug
2° homeostasis = coagulation cascade (resulting in production of the homeostatic plug)
3° homeostasis = fibrinolysis (break down of homeostatic plug) and regulatory mechanisms

Question 10

explain vasocontriction for 1° homeostasis. what is the goal of this process? how is it triggered further?

Answer 10

• relflex initiated at the site of injury
• to impede the amount of blood loss early on
• damaged endo cells trigger this further by releasing factors like endothelin & von Willerbrand factor (vWF)

Question 11

what does vWF do?

Answer 11

binds collagen in the exposed subendothelium

Question 12

explain the process of platelet plug formation

Answer 12

• injured endo cells release vWF
• circulating platelets have receptors for vWF
• results in platelet adhesion to the site of injury
• bound platelets activate, change in shape, releasing their granules/other contents which helps recruit additional platelets
• results in aggregation of platelets, forming the platelet plug

Question 13

is the platelet plug stable?

Answer 13

nah, only temporary seal (requires reinforcement)

Question 14

give a general explanation of the coagulation cascade and what is the main goal?

Answer 14

• a sequence of reactions resulting in the formation of fibrin and thus the homeostatic plug
• to prevent blood loss while the vessel repairs

Question 15

what is the primary component of the homeostatic plug? how does this element act?

Answer 15

• fibrin

- forms a cross-linked mesh which acts to stabilize platelet plug and trap erythrocytes & leukocytes in the process

Question 16

is the homeostatic plug stable

Answer 16

yes very

Question 17

what are coagulation factors?

Answer 17

-often enzymes, in the inactive (zymogen), form that circulate the blood and help with blood clot formation

Question 18

how are zymogens activated? where can this activation occur?

Answer 18

• by a procoagulant complex (which needs an active enzyme, a scaffolding cofactor (for position) and an inactive zymogen)
• the zymogen becomes an active enzyme and they cycle continues (snip aa which changes protein confirmaiton)
• can only occur on a procoagulant surface
• FIX –> FIXa (activated)

Question 19

explain how the coagulation cascade is initiated

Answer 19

• injury exposes the SM layer of vasculature which contains tissue factors (TF)
• interaction between TF and FVII initiates the coagulation cascade

Question 20

explain what happens once the coagulation cascade has been initiated

Answer 20

-clotting factors (which are circulating plasma zymogens) undergo a series of proteolytic activations resulting in fibrin

Question 21

what are the pathways of the coagulation cascade?

Answer 21

the intrinsic, extrinsic and common pathways

Question 22

what is FXa, how is it activated, and what does it do?

Answer 22

• can activated by the intrinsic and extrinsic pathway tenase complexes (which consist of an enzyme, a cofactor and a zymogen substrate)
• first clotting factor of the common pathway
• converts prothrombin to thrombin, which converts fibrinogen to fibrin

Question 23

does fibrin circulate in the blood?

Answer 23

nope

Question 24

what propogates the coagulation cascade?

Answer 24

positive feedback
(from thrombin to FXI, FVIIIa and FXIIIa)
(8,11,13)

Question 25

what are the characteristics of the extrinsic pathway?

Answer 25

- sparks the pathway in repsonse to injury | - produces some fibrin

Question 26

what are the characteristics of the intrinsic pathway?

Answer 26

- amplification ("work horse") - where most of coagulation occurs & most fibrin produced - important - without this pathway extrinsic pathway could not produce enough fibrin to create a stable homeostatic plug

Question 27

what is fibrinolysis?

Answer 27

enzymatic process of breaking down cross-linked fibrin into its degradation products

Question 28

why is fibrinolysis important?

Answer 28

- controls the size and spread of fibrin clot | - removes clot completely once damage is repaired

Question 29

explain the fibrinolysis pathway

Answer 29

- involves plasminogen activators that convert plasminogen to plasin - plasmin breaks down the clot into its degradation products - these products inhibit thrombin (inhibiting production of fibrin) - this prevents the homeostatic plug from reforming

Question 30

how is fibrinolysis controlled?

Answer 30

-once the clots been broken down plasminogen activator inhibitors (PAI) inhibit uPA and tPA (which are responisble for converting plasminogen to plasmin)

Question 31

explain the role of nitric oxide in negative regualtion of 1° homeostasis

Answer 31

healthy endo secretes NO to prevent platelet adhesion and aggregation

Question 32

explain the role of prostacyclin in negative regualtion of 1° homeostasis

Answer 32

healthy endo secretes prostacyclin (lipid molecule) to prevent platelet adhesion and aggregation

Question 33

explain the role of CD39 in negative regualtion of 1° homeostasis

Answer 33

- healthy endo expressess CD39 (a transmembrane ATPase) that catalyzes the dephosphorylation of ATP - this prevents platelet activation

Question 34

explain the role of tissue factor pathway inhibitor (TFPI) in negative regualtion of the coagulation cascade. what produces TFPI?

Answer 34

- TFPI inhibits the extrinsic pathway to prevent further input from the intrinsic pathway - TFPI is produced by endo cells and megakaryocytes

Question 35

explain the role of antithrombin in negative regualtion of the coagulation cascade. what produces antithrombin? is it found in circulating plasma?

Answer 35

- interacts w heparin/heparin-like molecules found on the surface of endo cells to inactivate various coagulation factors (including FVII, FIX, X, XI, FIIa (thrombin)) - produced by hepatocytes in the liver - found in circulating plasma

Question 36

explain the role of protein C in negative regualtion of the coagulation cascade. what is protein C activated by?

Answer 36

- activated by thrombin bound to thrombomodulin | - protein C needs protein S as a cofactor to mediate proteolytic inactivation of FVIIIa and FVa

Question 37

how do we diagnose blood disorders?

Answer 37

- measuring levels of protein in a plasma sample | - need to centrifuge sample to separate cellular components from the plasma

Question 38

what is crucial when taking blood samples and why?

Answer 38

- tubes must be coated with anticoagulant (e.g. EDTA) | - prevents blood from clotting