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Unit 12 > Blood coagulation 1 > Flashcards

Blood coagulation 1 Flashcards

1
Q

What is meant by haemostasis?

A

Blood - halting or blood clotting
Aims to stop/prevent haemorrhage whilst ensuring sufficient flow of blood.

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2
Q

What are the three dimensions of haemostasis?

A

Cellular - platelets
Humoral - coagulation cascade
Tissue - vessels ‘Vasoconstriction’

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3
Q

What is the consequence of too much haemostasis??

A

Excessive = thrombosis. In arteries this is due to plateles and can cause coronary thrombosis or thrombitc stroke. In veins this is due to coagulation and cause cause DVT/PE

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4
Q

What is the consequence of not enough haemostasis?

A

Haemorrhage = bleeding
Can occur due to trauma or a bleeding diatheesis such as haemophilia or von Willebrand disease.

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5
Q

What is the role of endothelial cells in haemostasis?

A

Produce vasoactive mediators - NO, PGI2 and endothelin - balance determines diamter of blood vessels
Also produce haemostatic agents such as von Willebrand Factor.

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6
Q

Explain how blood vessel damage affects endothelial cells and leads to haemostasis?

A

Is exposed to a pro-thrombotic mediator

Decreased production of NO and PGI2
Increased production of endothelin
Leads to vasoconstriction.

Produce von Willebrand factor which aids platelet aggregation

Loss of NO and PGI2 also aids platelet aggregation.

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7
Q

What is von Willebrand Disease?

A

Most common bleeding disorder
Genetic mutation for Deficient or dysfunction von Willebrand factor
Results in inability for platelet aggregation leads to increased risk of bleeding
Is treated for desmopressin.

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8
Q

What factors help activate platelets?

A

ADP
Thrombin
Thromboxane
Binds to recepotrs on the surface of platelets encourage to undergo conformational change to release granules, and cross links many platelets together.

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9
Q

What is the role of thrombin?

A

Activates platelets
Cleaves fibrinogen to fibrin
Cleaves plasminogen to plasmin.

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10
Q

What are some different anti-coagulant drugs?

A

Dabigatran
rivaroxaban
Heparin, dalterparin, fondaparinux
Warfin
Citrate and EDTA

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11
Q

What are some different fibrinolytic drugs?

A

Alteplase

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12
Q

What are some different antiplatelet drugs?

A

Aspirin
Dipyridamole
Clopridogel
Ticagrelor
Tirofiban

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13
Q

What are some examples of procoagulant drugs?

A

Tranexamic acid.

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14
Q

What is fibrinogen?

A

Is also known as factor 1 in the coagulation cascade
Is a soluble glycoprotein synthesized by the liver
Is found mainly in the plasma and in some platelet granules.

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15
Q

What is the function of fibrinogen in haemostasis?

A

Has a bifunctional receptor so can bind to two platelet molecules at once
This cross-links platelets contributing to platelet aggregation

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16
Q

What is fibrin?

A

Also known as factor 1a in the coagulation cascade
Formed by the action of thrombin on fibrinogen
Is an insoluble protein
Spontaneously polymerises forming fibrin clots - contributes to coagulation by stabilises the platelet plug found in secondary haemostasis.

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17
Q

What is a fibrin protofibril?

A

Resulting product of fibrin polymerisation.

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18
Q

What is prothrombin?

A

Also known as factor 2 in the coagulation cascade
A zymogen or inactive enzyme
Soluble plasma protein
Vitamin K dependent factor
Contains Gla residues which are negatively charged so bundling strongly to Ca2+

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19
Q

What is thrombin?

A

Also known as factor 2a in the coagulation cascade
Active enzyme
Formed by the cleavage of prothrombin.
Role in cleavage of alpha and beta chains of fibrinogen
Activates platelets via PARs.

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20
Q

What drugs target thrombin?

A

-gatran drugs

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21
Q

What is the use of the drug dabigatran etexilate?

A

Class = direct oral anti-coagulant or direct thrombin inhibitor
Chemistry: pro-drug, non-peptide, small molecule
Pharamacology: targets thrombin FIIa, acts as competitive reversible inhibitor.
Physiology: anticoagulant, by decreasing fibrin formation and decreasing thrombin-induced platelet aggregation
CLinical: treatment or prophylaxis for DVT and PE.

22
Q

What is the use of hidrudin and desirudin and why is this relevant to their origin?

A

Are anti-coagulants by inhibiting thrombin
Originate from leeaches - prevent blood from coagulation in order to better drink it.

23
Q

What is factor X?

A

May also be called a Stuart-Prower Factor
Is an inactive enzyme or zymogen
Is a plasma glycoprotein
Is a vitamin K dependent factor
Contains Gla residues which are negatively charged so bind strongly to Ca2+

24
Q

What is factor Xa?

A

Is an active enzyme
Serine protease
Formed by action of FVIIa or FIXa at FX.
Forms a complex with factor FVa to cleave prothrombin.

25
Q

What drugs target factor Xa?

A

-xaban drugs
Prevent cleavage or prothrombin to thrombin - prevent platelet aggregate and fibrin production

26
Q

What is the co-enzyme comple with factor Xa in the coagulation cascade?

A

Co-enzyme FVa
Also requires Ca2+ (which bind to FXa negaticly charged glu sites) and phospholipid surface.
Cleaves prothrombin to thrombin

27
Q

What is factor V?

A

Also known as proaccelerin
Is an inactive co-factor
Plsam glycoprotein
Monomer
Can be converted to active form accelerin.

28
Q

What is factor Va?

A

Also known as accelerin
Is an active co-factor in coagulation cascade
Formed by action of thrombin on FV - hence is a cleavage dimer held together non-covalently by Ca2+.

29
Q

What is the role of factor Va?

A

Forms complex with FXa
Also requires (Ca2+ and phospholipids)

This complex cleaves prothrombin to thrombin.

30
Q

What is the use of the drug rivaroxaban?

A

Class: is a direct oral anti-coagulant, direct factor Xa inhibitor
Chemistry: small molecule
Pharmacology: targets FXa (prothrombinase complex), acts as a competitive inhibitor
Physiology: anti-coagulant decreases thrombin generation
Clinical: treatment or prophylaxis for DVT and PE

31
Q

What is a prothrombinase complex?

A

Is factor Xa and Ca2+ and PL that converts Factor 2 to Factor 2a
Or
prothrombin to thrombin

32
Q

What is meant by the extrinsic tenase?

A

The extrinsic pathway of coagulation cascade
Tissue factor (FIIIa) converts FVII to FVIIa
Converts FX to FXa
Activation of factor ten hence tenase.

33
Q

What is meant by the intrinsic tenase?

A

The intrinsic pathway
Factor XIa converts IX to IXa
IXa with calcium ions and PL, and co-factor VIIIa this converts FX to FXa

34
Q

What is the mutation underpinning Haemophilia A?

A

Mutation results in deficient or dysfunction VIII.
Hence decrease FVIIIa, lack of this co-enzyme means unable to react alongside FIXa with Ca2+ and PL,
so factor X is not converted to FXa.

35
Q

What is factor IX?

A

Trigger of intrinsic factor of coagulation cascade
Also known as Christmas Factor
Is a zymogen or inactive enzyme
Is a plasma glycoprotein
FXIa will convert to FIXa, cleavage converts from monomer to a dimer.
Is a VK dependent factor
Contains Gla residues which have a strong negative charge which binds to Ca2+.

36
Q

What is factor VII?

A

Trigger of extrinsic factor of coagulation
Is a zymogen or inactive enzyme
Is a plasma glycoprotein

Is converted to FVIIa by FX, XIIa, IIa, changes from a monomer to a dimer
Is a vitamin K dependent factor
Contains Gla residues which are highly negative charged, which binds to Ca2+.

37
Q

What is factor III in the coagulation cascade?

A

Also called Tissue factor
Is a transmembrane glycoprotein
Is a co-factor.

Is expressed on sub-endothelial tissues
Expression is increased on endothelium and monocytes by TNF during inflammation
Forms a complex with FVIIa in order to cleave factor X

38
Q

What coagulation factors require calcium ion in order to become activated?

A

Factor X
Factor VII
Factor IX
Factor 2 or prothrombin

39
Q

What are the different co-activation complexes that form in the coagulation cascade?

A

Cell membrane bound tissue factor cleaves and binds to FVII(a), this complex can then cleaves FX to form FXa

Factor IXa and factor VIIIa also form a complex that cleaves facot X to factor Xa.

Factor Xa and factor Va to cleave prothrombin to thrombin.

40
Q

What is heparin?

A

The first anticoagulant
Is an glycosaminoglycan (GAG) consisting of polysaccharide units that vary in the density of sulfates and size.
When highly sulfate density is heparin and has a strong negative charge.

41
Q

What is the difference between heparin and heparan?

A

Hepatin - more dense in sulfates (more sulfates per disaccharide) so has a stronger negative charge, is found in mast cell along with histamine

Heparan - has fewer sulfates per disaccharide, are formed by post translational modification for example from syndecans, these proteins are known as heparan sulfate proteoglycans.

42
Q

What are the different repeating disaccharides in heparin?

A

Major repeatig disaccharide - Iduronic acid and GlcNS.

Minor repeating disaccharide - Iduronic acid or Glucaronic acid and
N-acetylglucosamine
These are brought together to form heparin molecules

43
Q

What is unfractionated heparin?

A

Contains polymers ranging from 6-80 repeating disaccharide with a Molecular weight from 3,000 to 4,000 Daltsons.

44
Q

What are the ethical issues around heparin?

A

Mostly isolated from animal sources
Tends to by porcine intestinal mucosa as the source
This has issued around informed consent when patients may have dietary or religious reasons to not consume pork.

45
Q

What is Low Molecular Weight Heparin?

A

Short chain polysaccharides dervied from the splitting of unfractionated heparin.
MW ranges from 5-8KDa
Intended to give more consistent response with fewer adverse affects.

46
Q

What are some example drugs that are low molecular weight heparins?

A

Dalteparin
Tinzaparin
Enoxaparin

47
Q

What is the target of unfractionated heparin and low molecular weight heparin?

A

**
Antithrombin 3
Binds to motif on antithrombin 3.
Heparin binding domain is made from five polysaccharide termed fondaparinux.
Causes a conformational change in antithrombin three that causes it to block FXa.

48
Q

What is anti-thrombin 3?

A

Is a plasma protein
Acts as a serine proteainse inhibitor
Inhibits FIIa (thrombin), alongise IXa, Xa, XIa, XIIa.
Activity is greatly increased by heparin

49
Q

How does anti-thrombin 3 inhibit FX?

A

When heparin fondaparinux binds to anti-thrombin 3 causes conformational change in anti-thrombin 3
This conformational change causes a loop of anti-thrombin 3 to project and block the active site of FXa heavy chain

50
Q

How are factor VII and Factor X complex recruited to the platelet cell membrane?

A

Localised to membrane of active platelets by carboxy-glutamater residuces bound to Ca2+ which can then bind to negatively surface membrane proteins.

51
Q

What are the key differences between LMWH and heparin?

A

Heparin is bigger molecules than fondaparinux/LMW heparin
Heparin bound to antithrombin 3 can inhibit FIIa and FXa. Inhibit FIIa as can bind to alongside AT3 required to bring together to ensure inactivation
However, LMWH and fondaparinux bound to ATIII can only inhibit Xa, as can not also bind FIIa.

Note FXa does not need to be interact with heparin to be activated.

52
Q

Describe the difference in structure between heparin/LMWH and fondaparinux?

A

Fondaparinux is a synthetic pentasaccharide sequence that closely mimics the natural pentassaccharide sequence in heparin.
Hence both are able to bind to anti-thrombin 3.

LMWH is a fractionated heparin (less other stuff) but still contains the same pentassacharide sequence as heparin.

Unit 12 (23 decks)

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