platelets and haemostasis Flashcards
1
Q
what do endothelial cells do when intact? when injured?
A
- contributes to preventing clots
- promotes clotting on exposed basement membrane
2
Q
what is extravasation?
A
active movement of fluid out of blood vessels
3
Q
what is haemostasis? 7
A
- a process which causes bleeding to stop
- clotting
- keeps blood within a damaged vessel
- opposite is haemorrhage
- first stage of wound healing
- endothelium secrets inhibitors of haemostasis normally
- when injured, the endothelium stops secreting inhibitors and instead secretes von willebrand factor
4
Q
explain platelets for primary haemostatic plug due to vessel wall injury? 3
A
- platelet adhesion
to exposed collagen in the basement membrane - platelet activation
exocytose dense granules (serotonin, ADP, calcium)
-platelet aggregation
stimulated by ADP, blocked by prasugrel, via fibrinogen
5
Q
what does coagulation do for clotting? 3
A
- makes a meshwork on the clot
- enzyme cascade- each activates the next enzyme
- part of coagulation requires platelets membrane
6
Q
what does vasoconstriction do for blood clotting? 4
A
- platelets release vasoconstrictors and pro-thrombotic agents
- serotonin
- ADP
- thromboxane A2
7
Q
what happens if you go down the common myeloid progenitor pathway? 2
A
- it can become a megakaryocyte which is found in the bone marrow
- each one will produce many thrombocytes (platelets)
8
Q
what is thrombocytopenia?
A
low platelet count in the blood
9
Q
what is platelet activation? 5
A
- exocytose + change shape + increased respiratory rate
- required for haemostasis
- extracellular ADP leads to the activation of P2Y receptor which causes a cation flow
- platelets release thromboxane A2 (TXA2)
- ADP causes positive feedback on platelets
10
Q
explain how coagulation works? 5
A
- many clotting factors circulate as inactive precursors
- factor Xa is activated version of factor X
- most are enzymes which will cleave other factors to activate them
- factor V and factors VIII are not enzymes, but are cofactors allowing enzymes to function which are also initially inactive
- initial activating factor is segregated
11
Q
what pathways lead to a blood clot? 3
A
- extrinsic pathway can make Xa
- intrinsic pathway can make Xa
- Xa works in the common pathway
- this leads to a clot
12
Q
what happens if blood is left standing in a lab? 2
A
- it will clot
- this is stopped with citrate or heparin
13
Q
what is plasma?
what is serum?
A
- fluid portion of blood
- fluid left after clotting, almost identical to plasma except its missing its fibrinogen, clotting factors II, V and VIII
14
Q
describe the common pathway? 5
A
- fibrinogen
- thrombin
- fibrin
- XIII +Ca2+
- fibrin cross-linked, is a stable clot
15
Q
explain the 2 coagulation cascades? 6
A
- extrinsic (tissue factor) pathway
- requires the secretion of tissue factor to occur
- initiation of coagulation
- intrinsic (contact activation) pathway
- all factors/ proenzymes are already in place
- amplification of process through positive feedback
16
Q
how do we activate thrombin? 3
A
- activated by factor Xa, but poorly
- factor Va is a cofactor of factor Xa
- together they activate thrombin well
17
Q
what are the pathways to activate factor X? 3
A
- extrinsic Xase- tissue factor (under endothelium) and factor VIIa
- intrinsic Xase- factor VIIIa and factor IXa
- thrombin also activates it via positive feedback
18
Q
explain positive feedback in coagulation?
A
-thrombin activates upstream cofactors to activate itself
19
Q
what are the coagulation factors? 11
A
- prothrombin group
- factors II, VII, IX, X
- enzymes
- vitamin K needed for synthesis
- requires Ca2+ for activation
- stable
- thrombin group
- factors I, V, VIII
- thrombin activates them
- V and VIII are cofactors
- factor I is fibrinogen
- increased in inflammation, pregnancy and with oral contraceptives
20
Q
what is vitamin K? 5
A
- clotting factor made by the liver
- liver dysfunction, cirrhosis or hepatitis can cause a clotting deficiency
- a class of related fat-soluble vitamins
- required to synthesise coagulation factors prothrombin II, VII, X (calcium dependent proteases)
- essential for gamma carboxylation of clotting enzymes
21
Q
what does fibrinolysis and inhibition of coagulation need to balance with?
A
clot formation
22
Q
what happens if there is too much fibrinolysis and inhibition of coagulation? 2
A
- blood vessel accumulating damage
- haemorrhage
23
Q
what happens if there is too much clot formation?
A
clot obstructs the vessel lumen
24
Q
what is plasmin? 4
A
- lyses fibrin- stops and destroys clots
- starts as inactive plasminogen (plasma protein made by the liver)
- requires tissue plasminogen activator (tPA) to mature
- tPA is on the surface of endothelial cells
25
what is protein C? 6
- coagulation inhibitor
- starts as an inactive enzyme
- made in the liver
- activated on surface of endothelial cells
- inactivates factor Va and factor VIIIa
- works with cofactor protein A to inactivate Va
26
what is antithrombin III? 6
- peptide in blood made by liver
- blocks the activity of thrombin
- heparin increases AT III activity
- heparin is reversible by protamine sulphate
- AT III deficiency leads to risk of thrombotic disease
- recombinant form of AT III is used medically for thrombotic disorders
27
what is a vitamin K deficiency? 5
- results in clotting insufficiency
- rare as vitamin K is made by bacteria of the large intestines and found in leafy green veg
- caused by GI disease or no fat absorption
- liver disease- no bile salts
- warfarin prevents the recycling of vitamin K and depletes the active vitamin K after a few days
28
what is haemophilia A? 5
- clotting disorder
- affects larger blood vessels
- wounds that bleed for days due to congenital lack of factor VIII
- X-linked, so only males have symptoms
- treat with purified factor VIII (expensive and rare)
- christmas disease/ haemophilia B is a lack of factor IX, the symptoms are the same
29
what is atherogenesis- a disease of inflammation? 7
- a disease of inflammation
- monocytes enter lesion and become macrophages and consume cholesterol esters
- become foam cells
- die and release contents which attract more monocytes
- cytokines
- chemo-attractants
- inflammation and haemostasis have synergistic effects on each other
30
what is atherogenesis- a disease of lipids? 4
- LDL deposits lipids in lesion
- cholesterol esters are non-aqueous which can make them solid/hard
- cholesterol esters are oxidised making oxygen radicals which makes them immunogenic
- oxidised lipids are consumed by macrophages which become foam cells, which explode, which attract more monoctyes
31
what is atherogenesis- a disease of the endothelium? 3
- endothelium expresses chemoattractant for monocytes to find and enter lesions
- when endothelium is lost, collagen stimulates coagulation, endothelium normally covers the collagen and the basement membrane
- when endothelium is lost, the vessel cannot control it dilation as it cannot produce NO
32
explain pharmacological control of blood clotting? 3
- anti-platelet agents block platelet activation which makes it good for treating arterial disease
- anti-coagulants block production or activity of clotting factors and are used to treat venous disease
- fibrinolytics are used to dissolve fibrin in arterial disease
33
describe antiplatelet agents? 8
- prevent clotting in arteries where anticoagulants have limited effects
- used in acute coronary syndromes
- aspirin is a cyclo-oxygenase (COX) inhibitor
- blocks the formation of thromboxane A2 in platelets
- lengthens bleeding time
- does not increase coagulation time
- prophylaxis for MI
- ADP receptor inhibitors= prasugrel/ clopidogrel
34
describe anti-coagulants? 7
- prevent clotting in veins and low-pressure pulmonary system
- deep vein thrombosis
- pulmonary embolism
- heparin inhibit coagulation with ATIII by inhibiting factor Xa
- novel oral anticoagulants (NOACs)
- dabigatran (thrombin inhibitor)
- rivaroxaban (factor Xa inhibitor)
35
describe fibrinolytics? 6
- clotting in arteries (high pressure)
- used during acute coronary syndromes
- tissue plasminogen activator (tPA)
- streptokinase
- urokinase
- also called thrombolytic drugs
