Thrombosis: haemostasis in the wrong place Flashcards
(68 cards)
1
Q
What does coagulation prevent?
A
Coagulation prevents blood loss
2
Q
What does inflammation activate?
A
Inflammation activates coagulation which promotes inflammation
3
Q
What type of response is coagulation?
A
Coagulation is an inflammatory response
4
Q
What can Ischemia’s of the brain be caused by?
A
Embolic stroke either from the carotids or heart
5
Q
What is primary haemostasis?
A
Aggregation of platelets
6
Q
What is secondary haemostasis?
A
The conversion of fibrinogen into fibrin
7
Q
Briefly describe what occurs in response to tissue damage
A
Primary platelets become activated –> Activated platelets clump together with RBCs
At the same time:
Secondary fibrinogen –> Fibrin –> Secondary blood clot –> The fibrin is cross-linked to form a solid blood clot
8
Q
What is important in coagulation?
A
The surface of platelets
9
Q
What do anticoagulants prevent?
A
Thrombosis
10
Q
What does fibrinolysis reverse?
A
Thrombosis
11
Q
Examples of anticoagulants
A
- Heperin
- Warfarin
- EDTA
12
Q
Describe the reactions that occur in thrombosis
A
- Aggregation of platelets
- Fibrinogen is converted into Fibrin mesh by Thrombin (a protease)
- Thrombin converted from Prothrombin
13
Q
What two reactions constantly occur in the body to maintain a balance?
A
Thrombosis and Fibrinolysis
14
Q
Where do different types of thrombosis form?
A
In different kinds of vessels: arterial thrombosis forms in arteries and venous thrombosis forms in veins
15
Q
Where does arterial thrombosis result from?
A
Mostly result from atheroma rupture or damage to the endothelium (e.g. MI, stroke)
16
Q
What type of thrombosis is arterial thrombosis?
A
- Platelet-rich ‘white’ thrombosis
- Mostly primary
17
Q
What damage can arterial thrombosis cause?
A
May block downstream arteries
18
Q
What does venous thrombosis result from?
A
- Often results from stasis or a hyper-coagulant state (DVT)
19
Q
What type of thrombosis is venous thrombosis?
A
- Platelet-poor ‘red’ thrombus
- Mostly secondary
20
Q
What damage can venous thrombosis cause?
A
May move to lungs
- Very hypercoagulant state
- Can lead to immobilization of the legs
21
Q
What mechanisms are balanced?
A
Balance of:
- mechanisms for clotting
- mechanism for resistance to clotting
- mechanism for undoing clotting
22
Q
Describe the conflicting events that occur in the coagulation vs fibrinolysis balance
A
- The endothelial cells are the cells lining the lumen of the vessel
- Damage to the endothelium means that the sub-endothelial cells will be exposed
- The coagulation response will activate clotting/Von Willebrand factors and platelets will bind to it: CLOTS form
- Clots can be inhibited by: Antithrombin, Heparan (which binds to Antithrombin)
- Prostaglandin & Nitric Oxide: inhibits platelets causing vasodilation
- When the clot does form, Tissue Plasminogen Activator works on the Plasminogen gives D-dimers
23
Q
What is coagulation inhibited by?
A
- Prostaglandins
- Antithrombin and Heparan
- Nitric Oxide
24
Q
What is the role of tissue plasminogen activator?
A
- Converts plasminogen into plasmin
- Cleaves plasmin into D dimer (a fibrin degradation product)
25
What is the role of tissue factors?
Initiates clotting
26
What do Von Willebrand factors activate?
Activates platelets
27
Role of Anti-thrombin
inhibits clotting
28
Role of Nitric Oxide
Inhibits platelets
29
Role of Prostaglandin I2
Inhibits platelets
30
What are the three factors that make up Virchow's triad (things that will lead to clots)?
1. Stasis: static blood lacks kinetic energy and tends to clot
2. Hyper-coagulant state: eg. infection/sepsis; genetic predisposition; drugs (e.g. HRT)
3. Endothelial damage: e.g. surgery or cannula
31
What is the role of valves in veins?
Valves prevent the backflow of blood
32
What is the role of muscles in veins?
Contraction of nearby muscles squash the veins, acting as a pump and returning the blood back to the heart
33
What can increase the risk of stasis?
Blood tends to eddy around valves, increasing the risk
34
How does Deep Vein Thrombosis occur?
- If venous return is blocked, the affected organ becomes congested with fluid
- Increased hydrostatic pressure, so more filtration: which pushes fluid out
- The risk is that the thrombosis might be dislodged and make its way back to the heart
35
What are the four possible fates of a thrombus?
1. Resolution: i.e. thrombolysis (breakdown of the thrombus)
2. Embolism: i.e. thrombus moves to another location and blocks the vessel, usually a smaller vessel preventing blood flow
3. Organised: i.e. becomes covered by endothelium, in this case you won't even know if you have one because the vessel just becomes a bit narrower
4. Recanalized and organized: new vessel, just with more holes
36
What is there a higher risk of in proximal DVT and what are the symptoms?
- There is a higher risk of pulmonary embolism and post-thrombotic syndrome (pain, swelling, maybe even ulcers)
- these don't break off
37
What does distal DVT rarely cause?
- rarely cause pulmonary embolism
- rarely cause post-thrombotic syndrome
- if it occurs in the lower legs, not as serious because the vessels here are very small
38
What can a small venous thrombolus cause?
- Slight VQ mismatch or small infarct zone
| - May be asymptomatic
39
What can a large venous thrombolus cause?
- Saddle embolism blocking both pulmonary arteries
| - Can cause rapid death
40
What activates platelets?
von Willebrand factors on subendothelial cells
41
What do circulating VWF bind to?
exposed subendothelial cells
42
What can also express VWF?
Activated subendothelial cells
43
What do activated platelets release?
- Thromboxane A2 (TxA2)
- Adenosine diphosphate (ADP)
These induce receptors for fibrinogen
They behave in a paracrine/autocrine way
44
What does TxA2 and ADP bind to?
Bind to receptors on adjacent platelets and increase expression of the glycoprotein complex GPIIb/IIIa
45
How else can platelets be activated?
Can also be activated by thrombin, collagen and many other mediators
46
What is the role of fibrinogen?
Acts as a tether, holding platelets together (this is platelet aggregation, not blood coagulation)
47
What is fibrinogen and where does it remain?
Fibrinogen is the solid precursor to fibrin and is in the circulation
48
What occurs after platelet aggregation?
Once you have a clump of platelets, they form a negatively charged surface which is required for coagulation.
- Charged phospholipids
- Fibrinogen tethers
49
What is coagulation?
Coagulation is the conversion of fibrinogen tethers to fibrin and then the cross-linking of the fibrin clot
50
When is the extrinsic pathway most important?
In vivo
51
When is the intrinsic pathway most important?
It forms the basis of laboratory tests of coagulation, not so important in vivo, there is some interaction with the extrinsic
52
What occurs at each step during the coagulation pathway?
- Amplification of the signal at each step
- Multiple steps at which you can inhibit the process
- Small amounts of activated factors can have a big effect
53
What are the three coagulation pathways?
1. Intrinsic
2. Extrinsic
3. Common
54
Describe the common pathway of coagulation
1. Factor IXa activates Factor X by proteolysis to create Factor Xa
2. Factor Xa cleaves prothrombin to form thrombin (IIa)
3. Thrombin (IIa) is a protease that cleaves fibrinogen into fibrin. Fibrinogen is a large molecule present in plasma- once cleaved it becomes insoluble fibrin
4. Fibrinogen promotes blood clotting by forming bridges between, and activating blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor
TENASE & PROTHROMBINASE
5. Thrombin cleaves factors V and VII to give Va and VIIIa
6. Va and VIIIa together with plasma C2+ form:
* Tenase complex: VIIIa + IXa -> Xa
* Prothrombinase complex: Va + Xa -> Thrombin
- These assemble n the charged phospholipid surfaces of the activated platelets
CROSS-LINKING FIBRIN CLOT
7. Once enough thrombin has been generated, XIII is activated, which cross links the fibrin fibres into a solid clot
55
What is the GLA domain?
GLA domain is 10-12 glutamic acids in the N-terminus of the molecule converted to gamma-carboxyglutamic acid (GIa)
56
What is the formation of gamma-carboxyglutamic acid dependent on?
It is a vitamin K dependent process
57
What inhibits the production of carboxygutamic residues?
Warfarin inhibits the production of carboxygutamic residues
58
What is the significance of the common pathway?
It is the bulk of the coagulation pathway
59
What are the common pathway reactions easily overpowered by?
Inhibitors
60
Describe the extrinsic pathway
- Tissue factor is a receptor for VIIa, also bound to a negatively charged surface of platelet phospholipids, along with calcium
- Once activated, the VIIa activates Xa and the common pathway is initiated
- TF present on most subendothelial cells; exposed if the endothelium is damaged, ready for VIIa to bind to and initiate coagulation
* Major one happening in vivo and is triggered by tissue factor which activates factor VII and feeds into the common pathway
61
What is the intrinsic pathway activated by?
Activates when you put blood into a charged surface such as glass
62
Defects in extrinsic vs intrinsic pathway
- Defects in the factors of the extrinsic pathway have far larger physiological effects than mutations in the enzymes of the intrinsic pathway
- Laboratory tests distinguish between activating the intrinsic or extrinsic pathways in order to assess where the defect might be
63
What can thrombolytic agents such as tissue plasminogen activator be used for?
Some of these thrombolytic agents such as tissue plasminogen activator and related
compounds are used to treat strokes and myocardial infarctions
64
What can inhibit clotting?
Antithrombin
65
What is a clot broken down by?
Clot is broken down by plasmin which is activated from plasminogen by tPA
66
Where is antithrombin expressed?
antithrombin is expressed by endothelial cells
67
What does antithrombin inhibit?
antithrombin inhibits a lot of the enzymes in the coagulation cascade, but thrombin and Factor VII in particular
68
What does Heparan bind to and what does this cause?
Heparan binds to the enzyme inhibitor antithrombin III (AT) causing a confromational change that results in its activation
- The activated AT then inactivates thrombin, factor Xa and other proteases
