Haemostasis

Question 1

What is Haemostasis ?

Answer 1

Physiological process to stop bleeding, prevent further blood loss and maintain blood vessel integrity
-Abnormalities can lead to an increased risk of bleeding

Question 2

What does Haemostasis involve ?

Answer 2

1) Vasoconstriction
2) Platelet plug formation (primary haemostasis)
3) Fibrin clot formation (secondary haemostasis)
4) Fibrinolysis

Question 3

How is vasoconstriction achieved and what does this do ?

Answer 3

Endothelial cells release vasopressors (endothelin, prostaglandins, thromboxane A2 & catecholamines)
-Reduce blood flow to affect area
-Changes flow; Increased margination of RBCs so Platelets & White cells closer to the vessel wall
-Rapid but brief process

Question 4

What does the endothelium do under normal conditions ?

Answer 4

Endothelial cells provide a suitable environment to aid blood flow
-Control vasodilation and constriction with NO and endothelin (among others)
-Under basal conditions inhibitory effect on haemostasis

Question 5

How do endothelial cells inhibit haemostasis under basal conditions ?

Answer 5

Prevent platelet adhesion, aggregation and activation
-13-HODE
-Prostacyclin
-NO
-Ectonucleotidases

Inhibit coagulation
-Thrombomodulin
-Heparin like moelcules
-Tissue Factor Pathway Inhibitor (TFPI)

Question 6

What is Primary Haemostasis ?

Answer 6

The initial response; formation of platelet plug
-Requires Platelets, Von Willebrand Factor, Collagen

Platlets are fragments of megakaryocyte cytoplasm

Question 7

What is Von Willebrand Factor ?

Answer 7

Synthesized by endothelial cells (and megakaryocytes).
-Secreted in subendothelial matrix and some into circulation
-Damage to endothelium exposes collagen and vWF of the subendothelial matrix; incrased Platelet adhesion

Question 8

What does a platelet do once it is activated by Von Willebrand Factor ?

Answer 8

Some of these activate other platelets

Question 9

How do platelets aggregate

Answer 9

Question 10

What are Consequences of failure of Platelet Plug Formation ?

Answer 10

Spontaneous Bruising and Purpura
Mucosal Bleeding
-Epistaxes
-Gastrointestinal
-Conjunctival
-Menorrhagia
Intracranial haemorrhage
Retinal haemorrhages

Also heavy periods

Question 11

What are the steps of primary haemostasis ?

Answer 11

1) Exposure to collagen and vWF
2) Platelet adhesion
3) Platelet activation
4) Platelet aggregation

Question 12

What is Secondary Haemostasis ?

Answer 12

Fibrin Clot

Primary Haemostasis initiates haemostatic response
-Not sufficient on its own
-Requires production of fibrin to stabilise clot
-”Bricks and Mortar”
-Also uses coagulation factors

Question 13

Where are components of secondary haemostasis produced ?

Answer 13

Cloting factors are mostly synthesized in the liver
Exceptions
vWF – endothelial cells
FV – platelets and liver
FXIII – platelets & liver
Tissue factor

Vitamin K Dependant Factors are important

Question 14

What is the role of Vitamin K in secondary haemostasis ?

Answer 14

Vitamin K required to carboxylate glutamic acid and convert to active form
-Four Vitamin K dependant coagulation factors
-Deficiency/Liver Disease/Medication can impact FII, FVII, FIX & FX

K = Koagulationsvitamin.

Question 15

Describe formation of a fibrin clot

Answer 15

Factors stuck to platelets are produced in liver

fX goes to fVa and fXa

TF = tissue factor

Question 16

What does a clot look like ?

Answer 16

Activated platelets linked by fibronigen
Insolbe fibrin is cross-linked by Factor XIIIa to form an insoluble fibrin mesh around and through the platelets.

Question 17

What are Consequences of failure of Fibrin Clot Formation ?

Answer 17

No characteristic clinical syndrome
May be combined primary/secondary haemostatic failure
Pattern of bleeding depends on Single/multiple abnormalities and the clotting factors involved

Question 18

How is coagulation measured ?

Answer 18

Split into different divisions:

Measuring Primary Haemostasis is difficult, can do platelet count but this doesnt tell us their function, we can cound vWF

Question 19

Which molecules provide negative feedback on coagulation ?

Answer 19

Protein C
Antithrombin
Heparin Co-factor II
Tissue Factor Pathway Inhibitor (TFPI)

Question 20

How does protein C provide negative feedback of coagulation ?

Answer 20

Inhibits FVa and FVIIIa by proteolyses serine bonds
-Activated by thrombomodulin bound to thrombin
-Has protein S as co-factor ;helps bind to phospholipid surface (i.e. platelets)

(FVa and FVIIIa are co-factors for FXa and FIXa)

Question 21

How does antithrombin provide negative feedback of coagulation ?

Answer 21

A serine protease
-Thrombin and FXa (but binds to many coagulation factors)
-Anthrombin complex has a short half life and slow clearance
-Activity increased 2000-4000 fold by interaction with heparins

Question 22

How does heparin co-factor II provide negative feedback of coagulation ?

Answer 22

Heparin Co-factor II also inhibits thrombin and activity increased by heparins

Question 23

How does Tissue Factor Pathway Inhibitor (TFPI) provide negative feedback of coagulation ?

Answer 23

K2 domain binds to FXa and K1 domain binds to FVIIa:TF
-Potent inhibitor & regulator of initial coagulation burst
-Synthesized by endothelial cells; 80% in vessel wall and 20% circultation

Factor VIIa–Tissue Factor complex (FVIIa:TF)

Question 24

What is Fibrinolysis ?

Answer 24

Breakdown of fibrin by Plasmin
-Process initiated at the same time as thrombus formation

Question 25

How is fibrinolysis stimulated ?

Answer 25

Plasminogen binds to Fibrin -tPA secreted by damage endothelium, slowing converting Plasminogen to Plasmin -Rate increased in presence of fibrin -Much less efficient on non fibrin bound plasminogen

Question 26

How is fibrinolysis suppressed ?

Answer 26

TAFI -Activated by thrombin via thrombomodulin (Same as protein C) -Inhibits thrombolysis by removing C-terminal lysine from from fibrin, preventing Plasminogen and tPA binding.

Question 27

What are D-dimers used for ?

Answer 27

D-dimers are a fibrin degradation product; Indicates breakdown of cross-linked fibrin clot by plasmin -Raised D-dimer means fibrin formation + breakdown -Negative result is reliable against clot formation, positive result is non-specific as many things can raise them (without causing clots) ## Footnote Negative D-dimer = excellent for ruling OUT DVT/PE