Haemostasis

Question 1

What substances allow platelets to be under vascular control?

Answer 1

NO, TXA2 (thromboxane 2), PGI2 (prostaglandin 2)

Question 2

Describe the formation of a soft platelet plug after the damage of a blood vessel occurs

Answer 2

Damage to the blood vessel

Platelets exposed to collagen in ECM + thrombin

Platelets are activated and adhere

Mediators released by platelets

Aggregation of platelets + vasoconstriction (to reduce blood flow/loss)

Soft platelet plug forms

Question 3

Describe the initiation pathway of blood clotting

Answer 3

TF (tissue factor) + VII = VIIa:TF

which causes X => Xa with Ca2+ and PLD

Xa causes II (prothrombin) => IIa (thrombin)

Thrombin then activates platelets by converting fibrinogen to fibrin.

7-1-2

Question 4

Describe the amplification pathway of blood clotting

Answer 4

Thrombin causes a few things to happen:
It causes the cleaving of VIII:vWF to VIII and vWF

It also activates factors IX,X,V,VIII (5,8,9,10)
factors IXa + VIIIa => IXa:VIIIa (also called tenase) as it causes Xa + Va => Xa:Va (prothrombinase) with Ca2+ and PLD which converts II => IIa (thrombin) then there is a loop

(8:vWF, 5,8,9,10, 9:8, 10:5, 2)
(diagram)

Question 5

What effect does thrombin have in platelets?

Answer 5

Causes conversion of fibrinogen to fibrin; then fibrin mesh is produced

Question 6

What clotting factor causes crosslinking of fibrin monomers?

Answer 6

XIIIa, producing an irreversible + stable clot

Question 7

What effect does clotting factor XIIIa have on fibrin monomers?

Answer 7

Causes crosslinking of fibrin to form an irreversible and stable clot

Question 8

What two things needed to be considered in balance when deciding to use antiplatelet drugs?

Answer 8

Clot formation risk vs haemorrage risk

Question 9

Give some examples of antiplatelet drugs

Answer 9

Aspirin
P2Y12
GPIIb-IIIalpha

Question 10

How does asprin work as an antiplatelet drug?

Answer 10

There are two enzymes to know here: cycloxygenase 1 and 2.
COX-1 is expressed in platelets and produces TXA2
COX-2 is expressed in the endothelium and produces PGT2

TXA2 is a platelet agonist whereas PGT2 is a platelet antagonist.

Aspirin inhibits COX-1 therefore reduces the TXA2:PGT2 ratio, in turn reducing the platelet activity.

Question 11

Give some examples of P2Y12 antagonists

Answer 11

Ticagrelor, cangrelor, elinogrel

Question 12

What does P2Y12 do in blood clotting?

Answer 12

Causes full platelet aggregation and irreversible clot formation

Question 13

What are the types of GPIIb-IIIalpha antagonists?

Answer 13

Small antibody fragments

Small molecule inhibitors

Question 14

Give an example of a small molecule inhibitor GPIIb-IIIalpha antagonist

Answer 14

Eptifibatide

Question 15

Give examples of small antibody fragment GPIIB-IIIalpha antagonist

Answer 15

Abciximab, tirofiban

Question 16

Give an example of an anticoagulant therapy

Answer 16

Heparin - a sugar polymer which inhibits active factors IX,X,XI,XII and IIa
Used for prevention and rapid treatment

Question 17

What is the difference between unfractionated and LMW heparin

Answer 17

Unfractionated heparin:
+ cheap, effective, short half life, reversible with protamine
- varying polymer length so bioavailability varies - patient needs monitored, continuous infusion

LMWH:
+ better bioavailability, lower risk of HIT
-only partially reversible by protamine, expensive

Question 18

What is HIT

Answer 18

Heparin induced thrombocytopoenia; when factor IV binds to antibody - causes inappropriate activation of platelets

Question 19

Give an example of a thrombin inhibitor

Answer 19

Lepirudin

Question 20

What cytokines are released when the endothelium is damaged that can lead to blood clotting?

Answer 20

Bradykinin
Thrombin
Kallikrein

Question 21

How can prostacyclin help prevent inappropriate blood clot formation?

Answer 21

It is a platelet aggregation inhibitor

Question 22

How does the tissue factor pathway inhibitor prevent inappropriate blood clot formation?

Answer 22

By inactivating Xa

Question 23

How can activated protein C become activated and then prevent inappropriate blood clot formation?

Answer 23

Activated by thrombin-thrombomodulin

With cofactor protein S it inactivates Va and VIIIa