haemostasis

Question 1

What are the main roles of the haemolysis system?

Answer 1

The haemolysis system describe coagulation and blleding stop-designed to stop you from bleeding to death BUT if too strong can kill you with thrombosis

Question 2

What factors does a healthy blood contain?

Answer 2

Blood contains cells (RBC) but also plasma-in there many coagulation factors (eg: FVII) and regulatory factors to inhbit the response once its starts (eg: AT)
main players are von willibrand factor (vWF), F V-X, platelets
Collagen and tissue factor is subendothelial

Question 3

What is von willibrand factor

Answer 3

vWF is a small protein that binds collagen platelets and itself-forms large polymers that will bind to exposed collagen and allow platelets to bind/activate-circulate in blood

Question 4

What are platelets?

Answer 4

Platelets are cell fragments from BM megakaryocytes-no nucleus but filled with protein granules containing many things-circulate in blood
Key receptors include GP1ba which binds vWF, GP1a-2a and GPIV that bind collagen, PGI2 receptors, thromboxane receptors and P2Y12 that binds ADP
activation of these elads to release of Ca intraceullaralry and granule release

Question 5

Describe the steps in formation of primary haemolytic plug

Answer 5

As damage to endothelium happens-collagen is exposed-bloodbord vWF then unfolds and binds to collagen-
Platelets can bind the vWF and high speeds and agregates them-slow speed can also bind collagen + activated
Activated platelets can bind more vWF and repeat the process-until a complete plug is formed
Important: vWF, platlets, collagen
sufficient for small blood vessels and small cuts-but not large ones

Question 6

What is coagulation and where are the main players synthesised

Answer 6

Coagulation or secondary haemostasis consits in the formation of a fibrin mesh
Made with factors made from liver (FV, VII, IX X, and more)
Some endothelial fctors (VIII and vWF) and platelets

Question 7

Describe the coagulation cascade in leading to fibrin formation

Answer 7

Intrinsic and extrinsic path
Extrinsic-Tissue factor from damaged tissue helps activate FVII. FVIIa activates X. Xa forms Tenase complex. FVIIa can also act on FXI->FXIa
Intrinsic-XII->XIIa acts on XI->XIa, acts on IX to IXa. THis acts on X->Xa, making Tenase complex
Tenase complex, with co-factors FVIIIa and FVa makes Prothrombin to thrombin which makes fibrinogen (soluble) to fibrin (nonsoluble and cross links can be stengthened with FXIIIa)

Question 8

List the reason for the thrombin burst to be required

Answer 8

threombin brust helps the clot actually generate-if not, TFPI could inhbit it. TFPI
Makes a stronger, denser clot, more resistant to fibrinolysis
FXIII is activated by thrombin and cross links thrombin

Question 9

How does heparin acts to inhbit coagulation

Answer 9

Direct inhbition-binds blood Anti thrombin (AT), making a heparin, AT and Thrombin complex
This complex suddentl acts against coagulation-inhbiting XIa, IXa, Xa and thrombin in iself

Question 10

Describe the mechanism by which protein C down regulated thrombin generation

Answer 10

Once thrombin is activated, it can bind thombomodulin-receptor on endothelial cells-protein C as well
thrombin activated protein C, which complexes with protein S which inhbits the production of FVa and FVIIIa (co-factors of Tenase complex)

Question 11

How is coagulation localised to the damage

Answer 11

thrombin tries and continuing the clot and flow in the blood. There, Floating AT can inhbit it. heparins on healthy endothelial also helps
Similarly, the thrombodulin on healthy endothelial help creat protein C-inhbit cascade as soon as reaches healthy endothelial (which has it receptors intact)

Question 12

Describe the process of clot breakdown

Answer 12

again floating in blood, plasminogen and tissue plasmnogen activator. But normally, both dont find each other (even as cofactors)-but both bind fibrin and can meet there
Once met, Plasminogen activates plasmin, which then degrades fibrin (creating fibnrin degradation product)

Question 13

What are the chracteristic for abnormal bleeding related to coagulation problems?

Answer 13

Spontaneous, out of proportion, unduly prolong, restarts after apearing to stop
Easy bruising is also one, but 12% of population has that

Question 14

What are the main defects linked to primary haemostasis?

Answer 14

primary heamostasis needs collagen, vWF and platelets-therefore any disease in those can be bad
Collagen-steroid therapy, scruvy
vWF-genetic vWF disease
platelts-aspririn and drugs, but also thrombocyopenia

Question 15

What patterns of bleeding are associated with defects in primary haemostasis?

Answer 15

Immediate (no initial clot made), easy bruising, nsoebleed (long), gum bleeding, menorrhagia, aneamia, trauma bleeding, and petechiae (only for platelet-a lot of small micro bruises all over legs-vessels burst and never clog)

Question 16

How is haemophilia defined in terms of heamostasis

Answer 16

heamophilia is the opposite off heaemostasis-failure to generate fibrin stabilising the plug

Question 17

What are the most common exemples of secondary haemostasis defects?

Answer 17

Defects can be in anything generating fibrin-bad thrombin burst, bad mesh, no mesh
genetic causes-haemophilia (A=FVIII) (B=FIX)
Aquired: Liver disease (most coagulation made in liver)
drugs (warfarin-inhbit synthesis and platelets cannot make new proteins)
Dilution (as give blood to someone, has less factors to plug)
consumption (DIC-with generalised inflamation, tissue factor in veins=> causes coagulation within the blood, but not enough for real damage. But after a while, factor deplete, and then constant fibrinolysis depletes fibrinogen-widspead bruising, depositing of firbin within vessels

Question 18

What patterns of bleeding are associated with defects in secondary haemostasis?

Answer 18

Often delayed (because primary plug works), deeper (joint and muscle (eg:heamathrosis (hall mark of haemophilla), not from small cuts, no nosebleeds, heavy after trauma

Question 19

What are the main causes of excess fribrinolysis leading to a bleeding disorder?

Answer 19

Excess fibrinolytic (plasmin, tPA)-fribrin breaken down too fast-often due to drugs given-need to balance them
can be due to tumours producing too much
Can also be due to deficient antifibrinolytic (antiplamin deficiency, genetic)

Question 20

What are the main causes of anticoagulant excesses leading to a bleeding disorder?

Answer 20

usually therapeutic-give tio much herpain, thrombin, Xa inhbitiors, etc

Question 21

What is the definition of thrombosis?

Answer 21

Something along: intravascular coagulation, innapropriate coagulation-not preceded by bleeding
Can be arterial or venous

Question 22

What are the main effects of thrombosis?

Answer 22

Obstructed blood flow-in arteries-ischemia, MI, stoke,

In veins-pain and swelling (very painful) (eg: DVT)

Question 23

What is the definition and main effects of embolism

Answer 23

Migration of thrombus down stream
Venous emboli will migrate through heart to pulmanory system-low pressure there will make it lodge-loss part of lung (eg: DVT thrombus goin to lungs (like after a long lfight)
Aterial emboli-usually form in the heart, goes through and causes stoke/limb ischemia

Question 24

Describe the main trends and characteristics of pulmonary emboli prevalence

Answer 24

about 1-1000 - 10 000 per annum-incidence increases with age
About 10% of hospital deaths
DVT rises sharp with age, but PE even sharper (30% at 80)
5% mortality, often reccurent, and reallllly increased by thombophlebitic syndrome (scarred veins after long DVT)
Most common after coming in for surgery at hospital-dilution immobile and inflammation

Question 25

How can thrombosis risks be modelled?

Answer 25

genetic risk is like a baseline-where you start-then as you grow older/lifestyle, risk rise more or less sharply
Can get immediate events (such as sitting in plane for 24h) that causes a jump-and puts you over the threshold-get thrombosis
importantly, can be modelled better with VIrchow’s triad
Most thrombosis is due to combined risk-eg pregancy can increase coagulation AND the sterical change tightens blood vessels
Same with cancer
Other include surgery, inflammatory response

Question 26

Recall the 3 components of virchows triad, and which part contributes to which form of thrombosis

Answer 26

Virchows triad describe 3 components in trhombosis
Blood-factors in blood-motsly venous
Vessel wall-dominant in arterial
flow-complex, often in both
All these can be genetic or acquired

Question 27

What are the most common blood factor problems linked to thrombosis?

Answer 27

Can be upregulation of coagulation factors (FVIII, FII (thrombin), platelets (thrombocytosis) or other (FV leiden-genetic-FV has increased resistance to Protein C deactivation, 6.6% chance increase of thrombo)
or down regulation of anticoagulants(Antithrombin (50x increase), protein C (20% increase of thrombo), protein S)
these are all heterozygous-homo just die

Question 28

What are the most common vessel wall problems linked to thrombosis?

Answer 28

We dont actually know much because its hard to sample
But in general-protein that act against coagulation are on endothelial cells, such as thrombodulin, TF pathway inhbitior, heparin
Also linked with inflamation-malignancy, infferction, AID

Question 29

What are the most common flow problems linked to thrombosis?

Answer 29

Reduced flow in general (stasis) increased chances of venous thrombosis. turbulant flow too
Caused by surgery, frature, long haul flight, bed rest

Question 30

What are the clinical and lab signs of thrombophilia?

Answer 30

Clinical: thrombosis at young age, idopathic thrombosis, multiple thromboses, Thrimbosis while on antigoagulants
Lab: Identify AT deficienct, FV leiden, measure coagulation ( blood test)

Question 31

What are the main startegies to treat Venous thrombus?

Answer 31

Immediate treatment is to lyse clot: give tPA -then at high risk of bleed
Then try and limit reccurenc/extension/emboli
increase Anticoagulant (heparin); lower procoagulants (warfarin inhbit liver synthesis of factors)
Inhbit procoagulant (previledged nowadays-eg dibigatran)
Prefered method is prevention-assess any patient coming in for VTE risk and treat with stocking + heparin while in patients-because largest risks after surgery)

Question 32

What is TFPI

Answer 32

Tissue factor pathway inhbitor-deactivates XIa and can bind innactivated Xa to inhbit VIIa