Haemostasis Flashcards
What substances allow platelets to be under vascular control?
NO, TXA2 (thromboxane 2), PGI2 (prostaglandin 2)
Describe the formation of a soft platelet plug after the damage of a blood vessel occurs
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
Describe the initiation pathway of blood clotting
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
Describe the amplification pathway of blood clotting
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)
What effect does thrombin have in platelets?
Causes conversion of fibrinogen to fibrin; then fibrin mesh is produced
What clotting factor causes crosslinking of fibrin monomers?
XIIIa, producing an irreversible + stable clot
What effect does clotting factor XIIIa have on fibrin monomers?
Causes crosslinking of fibrin to form an irreversible and stable clot
What two things needed to be considered in balance when deciding to use antiplatelet drugs?
Clot formation risk vs haemorrage risk
Give some examples of antiplatelet drugs
Aspirin
P2Y12
GPIIb-IIIalpha
How does asprin work as an antiplatelet drug?
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.
Give some examples of P2Y12 antagonists
Ticagrelor, cangrelor, elinogrel
What does P2Y12 do in blood clotting?
Causes full platelet aggregation and irreversible clot formation
What are the types of GPIIb-IIIalpha antagonists?
Small antibody fragments
Small molecule inhibitors
Give an example of a small molecule inhibitor GPIIb-IIIalpha antagonist
Eptifibatide
Give examples of small antibody fragment GPIIB-IIIalpha antagonist
Abciximab, tirofiban
Give an example of an anticoagulant therapy
Heparin - a sugar polymer which inhibits active factors IX,X,XI,XII and IIa
Used for prevention and rapid treatment
What is the difference between unfractionated and LMW heparin
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
What is HIT
Heparin induced thrombocytopoenia; when factor IV binds to antibody - causes inappropriate activation of platelets
Give an example of a thrombin inhibitor
Lepirudin
What cytokines are released when the endothelium is damaged that can lead to blood clotting?
Bradykinin
Thrombin
Kallikrein
How can prostacyclin help prevent inappropriate blood clot formation?
It is a platelet aggregation inhibitor
How does the tissue factor pathway inhibitor prevent inappropriate blood clot formation?
By inactivating Xa
How can activated protein C become activated and then prevent inappropriate blood clot formation?
Activated by thrombin-thrombomodulin
With cofactor protein S it inactivates Va and VIIIa
