Vascular injury

Question 1

what thing cooperate in heamostasis

Answer 1

platelets, plasma proteins of the coagulation cascade, endothelial cells.

Question 2

what are platelets

Answer 2

discoid anuclear bodies produced by cytoplasmic fragmenattion of the megakaryocytes in the bone marrow. lifespan of about 7 days.

Question 3

what activates platelets

Answer 3

ECM proteins particularly collagens. exposed following endothelial damage.

Question 4

what do platelets adhere to in endothel damage

Answer 4

collage but mediated by Von willebrand factor. they then change their shape, shoot out long processes,and secrete chemicals like thromboxane A2, vasoactive amines (5HT) and ADP. promotes vasoconstriction and aggregation. a primary homeostatic plug is formed to temporarily fill the gap.

Question 5

what happens after formation of the primary homeostatic plug?

Answer 5

platelet contraction, close apposition of the membranes and eventual fusion.

Question 6

what mediates the phase of aggregation and fusion

Answer 6

a battery of receptor-ligand interactions and cell adhesion molecules :

• integrins (esp alpha2bbeta3)
• JAMs, ESAMs (endothelial cell-specific adhesion molecule)
• kinase-ligand combination of the eph and ephrin families

Question 7

what causes the contraction of the platelet aggregation

Answer 7

the ntegrins and the eph/ephrins via cytoskeletal alteration via myosin dependent contraction.

Question 8

what is purpura

Answer 8

bleeding from skin capillaries due to reduced platelets.

Question 9

what types of granules do platelets release

Answer 9

dens granules and alpha granules

Question 10

contents of alpha granules

Answer 10

PDGF
TGFbeta
factor 5, 8 and fibrinogen
PF4

Question 11

contents of dense granules

Answer 11

ADP
calcium
5HT
ADR

Question 12

what is the coagulation cascade

Answer 12

the series of proteolytic reactions through which circling inert zymogens are sequentially activated.

Question 13

describe the common coagulation pathway

Answer 13

factor 10 activated to factor 10a by the intrinsic and extrinsic pathways on a phospholipid surface such as platelets in the primary haemostatic plug.

• 10a complexes with activated factor 5a in the presence of calcium and then catalyses prothrombin to thrombin.
• thrombin then does a whole load of things including cleving activation peptides from fibrin to activate it and cause it to polymerise.
• thrombin also activates factor 13 which catalyses the formation of covalent intermolecular bonds between the fibrin monomers to stabilise it.
• thrombin also activates more platelets, and catalyses the activation of factors 5 and 8. (8 is part of the intrinsic pathway).

Question 14

what is the secondary haemostatic plug

Answer 14

the meshwork of crosslinked fibrin strands with fused platelets.

Question 15

what system disassembles the haemostatic plug

Answer 15

the fibrinolytic system. plasminogen is precipitated with fibrin in the interior of the thrombus . plasminogen is activated here into the active protease plasmin.

Question 16

what is the master regulator of the clotting cascade

Answer 16

thrombin!

Question 17

describe the extrinsic pathway

Answer 17

exposure of subendothelium exposes tissue factor which binds factor 7 and causes it to autoactivate to factor 7a.
- factor 7a with calcium and on a phospholipid membrane, activates factor 10 to 10a

Question 18

describe the intrinsic pathway

Answer 18

exposure of the subendothelium which is negatively charged. negative charge activates factor 12 to 12a.

• 12a activates prekallikrein to kallikrein which is anchored by HMW kininogen to the subendothelium.
• kallikrein does a number of things inc amplify factor 12 activation.
• factor 12 also activates 11 to11a which then cleaves its anchoring HMW kininogen to diffuse into the circulation and catalyse the activation of factor 9 to 9a in the presence of calcium.
• 9a complexes with 8a (released from VMF by thrombin) and calcium to activate factor 10 on phospholipids.

Question 19

so what is a blood clot

Answer 19

the fibrin mesh with the platelet plug and caught platelets and RBCs.

Question 20

how does normal endothelium inhibit clotting

Answer 20

1 - physical insulation
2 - enzymes
3 - chemical inhibitors

Question 21

7 things made by the endothelium to inhibit clotting

Answer 21

1 - NO and PGI2 (prostacyclin) - inhibit platelet activation
2 - antithrombin - on cell surface binds and inactivates thrombin. complex released and cleared by the liver
3 - tissue factor pathway inhibitor (TFPI) blocks activation of factor 10 by tissue factor
4 - thrombomodulin - on cell surface, changes the conformation of thrombin so its less able to cleave fibrinogen and instead becomes able to activate protein C in the circulation
5 - protein C inactivates factor 5 and 8.
6 - protein S - a cofactor for protein C.

Question 22

how do damaged endothelial cells promote coagulation

Answer 22

1 - exposed underlying tisses
2 - synthesising enzymes and chemicals such as
- Von willebrand factor - promotes platelet adhesion to proteins
- tissue factor (thromboplastin) which activates coagulation
- binding sites for factors 9 and 10.

Question 23

define a thrombus

Answer 23

a mass formed from blood constituents within the circulation during life. composed of fibrin, platelets, with entrapped RBCs and WBCs

Question 24

difference between a thrombus and a blood clot

Answer 24

a blood clot is formed in static blood and involves primarily the coagulation system, but without interaction with platelets and the vessel wall = glass in vitro and post mortem.

Question 25

how does a thrombus cause damage

Answer 25

either occlusion where it forms or by breaking off and obstructing elsewhere (embolism)

Question 26

what’s a clot

Answer 26

a soft, jelly like mass that’s an unstructured mixture of blood cells suspended in serum proteins.

Question 27

what’s virchow’s triad?

Answer 27

the three broad categories of factors that contribute to thrombosis-

1 - changes in vessel wall
2 - changes in blood flow
3 - changes in the constituents of the blood

Question 28

5 causes of changes to vessel wall for thrombosis

Answer 28

injury or activation due to -
1 - ischaemic hypoxia (endothelium lining the cardiac chamber following coronary artery disease)
2 - infection
3 - physical damage - rupture of atherosclerotic plaques, crushing veins, haemodynamic stress in hypertension.
4 - chemical damage - lipids, cigarette toxins, bacterial lipopolysaccharide
5 - immunological damage (deposition of complexes)

Question 29

changes in blood flow that cause thrombosis

Answer 29

disruption of laminar flow which causes

• platelets to contact endothelium
• impaired removal of procoagulants
• impaired deliver of anticoagulants
• direct injury of activation of endo

Question 30

causes of change in flow in arteries or cardiac chambers

Answer 30

turbulence is important. due to -

• narrowing (atherosclerosis)
• aneurysm
• infarcted myocardium
• abnormal cardiac rhythm
• valvular heart disease

Question 31

causes of changes in flow in veins

Answer 31

stasis is important. due to

• right sided heart failure
• immobilisation
• compressed veins (long flights or bed rest)
• varicose veins
• increased viscosity of blood (sickle cell, dehydration)

most commonly affected = pelvic veins, deep and superficial leg veins.

Question 32

causes of changes to blood contents that cause thrombosis

Answer 32

increases tendency to coagulate.

• genetics - deficiency of antithrombin 2 or protein C
• acquired - tissue damage (trauma, MI)
• post-operative state
• malignancy
• cigarette smoking
• elevated blood lipids
• oral contraceptive therapy

Question 33

what, generally, does the appearance of thrombi depend on?

Answer 33

the rate of blood flow at the site of formation

Question 34

appearance of thrombi in arteries or cardiac chambers

Answer 34

compact, granular and firm.
contain laminations - pale branching layers of fibrin/platelets and darker layers of erythrocytes.
-laminations = lines of Zahn

Question 35

appearance of thrombi in veins

Answer 35

pale head with a long red tail

little lamination. red tail = enmeshed RBCs

Question 36

6 outcomes of a thrombus

Answer 36

1 - lysis - fibrinolytic system. use streptokinase to accelerate
2 - propagation - usually in relatively stagnant blood
3 - stenosis or occlusion of vessel
4 - organisation - inflammatory reaction then organisation
5 - infection
6 - embolisation

Question 37

what happens in organisation of a thrombus

Answer 37

inflammatory reaction
1 - retraction of thrombus and partial digestion by leukocyte enzymes
2 - monocyte/macrophage phagocytosis of resultant debris
3 - overgrowth and ingrowth of endothelium to form new vascular channels.
4 - migration of smooth muscle and fibroblasts
5 - synthesis of ECM eg collagen
either the thrombus will be incorporated into the vessel wall and cause stenosis, or the new vascular channels will anastomose, dilate and restore flow (recanalisation).

Question 38

define an embolus

Answer 38

an intravascular mass carried by the blood flow from point of origin to a distant site.
inc - thromoboembolism, fat, air, atheromatous debris, bone marrow, amniotic fluid.
they cause stenosis, sichaemia and infarction

Question 39

result of vein emboli

Answer 39

lodge in a pulmonary artery causing hypoxia, pulmonary infarc, reduce CO, right heart failure, shock and death.

Question 40

what is pyaemia

Answer 40

can be caused by infected emboli lodging elsewhere and forming an abscess.