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Unit 12 week 2 (Sam) > Blood coagulation > Flashcards

Blood coagulation Flashcards

1
Q

Haemostasis, porocesses that

A

1) stop haemorrhage
2) prevent haemorrhage
3) maintain blood flow

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2
Q

Primary haemostasis includes

secondary includes

A

1) vasoconstriction
2) haemostatic plug formation

Activation of clotting factors to form a thrombus

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3
Q

Haemostasis is carried out by which mechanisms

A

1) cellular= platelets
2) Humoral = coagulation
3) Tissue = vessels

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4
Q

Disordered haemostasis

A

Thrombosis- excess or innappriate clotting

1) Arterial caused by platelets

Coronary thormbosis, thrombotic stroke

2) Venous caused by coagulation

DVT and PE

Haemorrhage- excess or innappropriate bleeding

Trauma or bleeding diatheses

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5
Q

bleeding diatheses

A

tendency to suffer from a particular kind of disease- in this case bleeding.

e.g. haemophilia, von Willebrand disease

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6
Q

Virchow’s triad

A

3 causative factors of thrombosis:

1) Coagulation factors- humoral
2) Platelets (cellular)
3) Blood vessels

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7
Q

How do blood vessels contribute to blood control?

A

Produce vasoactive mediators and haemostatic agents

Vasospasm (vasoconstriction)

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8
Q

Coagulation cascade

A
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9
Q

Intrinsic pathway

A

XIIa (12)

XIIIa (8) + XIa (11)

Va (5) + IXa (9)

IIa (thrombin)

Ia (fibrin)

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10
Q

Extrinsic pathway

A

Initial damage

IIIa (3)

VIIa (7)

Xa (10)

IIa (thrombin)

I (fibrin)

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11
Q

Why is it phsiologically beneficial to have so many steps in the coagulataion cascade?

A

The more steps you have, the more control you have over it.

This is particulalry important where there is positive feedback and you don’t want to trigger this process in an unijured are

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12
Q

Fibrinolytic drug example

A

Alteplase

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13
Q

Examples of antiplatelet drugs

A
  1. Aspririn
  2. Clodidogrel
  3. Ticagrelor
  4. Tirofiban
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14
Q

Fibrinogen

A

Factor 1

Soluble glycoprotein synthesised by the liver

Heterohexamer (2x a chain and 2x B and 2x Y)

Acts as a bifunctional ligand for aIIbB3 integrin (glycoprotein IIb/IIIa) on platelets

Mostly found in plasma, some found in platelet granules

Target for drugs

Cross-links platelets –> aggregation

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15
Q

Fibrin

A

Factor Ia

Insoluble protein

Formed by action of thrombin on a and B chains of fibrinogen

Fibrinopeptide A and B

Spontaneously polymerizes –> forms fibrin clot–> coagulation

Entangle platelets, building up a spongy mass that gradually hardens and contracts to form the blood clot.

Hardening process stabilized by FXIII (fibrin-stabilizing factor)

As fibrin is formed it binds to thrombin- limiting the thrombin that is active

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16
Q

Fibrinogen –>?

A

Fibrinogen –> fibrin monomer–> finrin polymer –> fibrin fibril

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17
Q

Glycoprotein IIb/IIIa (integrin αIIbβ3)

A

Integrin complex found on platelets

Receptor for fibrinogen and von Willebrand factor

Aids in platelet activation

formed via calcium-dependent association of gpIIb and gpIIIa, a required step in normal platelet aggregation

Platelet activation by ADP (blocked by clodipogrel) causes conformtational change in integrin αIIbβ3 receptors to allow FII binding

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18
Q

Prothrombin

A

Factor II

Zymogen, soluble plasma protein

monomer

Vitamin k-dependant factor

10y-carboxyglutamate residues confer a strong negative charge which binds to Ca2+

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19
Q

Thrombin

A

Factor IIa

Active enzyme

Serine protease

Formed by action of FXa enhanced by FVa

Co-translationally modified in a vitamin k dependant reaction to have a Gla (inhibited by warfarin or vit K deficiency)

Activates many other factors, most notably fibrinogen by cleaving a and B chains

Target for gatran drugs

Engages in negative feedback

Made of a light and heavy chain

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20
Q

What does thrombin convert?

A

FXI–>XIa

FVIII–>VIIIa

FV–> Fva

fibrinogen –> fibrin

XIII–> XIIIa

Actiavtes platelets via proteinase activated receptors

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21
Q

Negative feedback mechanisms of thrombin

A

Bound to thrombomodulin (endothelial membrane protein), activates protein C, an inhibitor of the coagulation cascade.

Stimulates production of antithrombin (serine protease inhibitor)

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22
Q

Dabigatran etxilate

A

Class: NOAC(novel oral anticoagulant)

Direct thrombin inhibotr

Chemistry: Prodrug, small molecule, active compound

Pharamacology:

Target- thrombin

Activity- competitive, reversible inhibitor

Physiology: Anticoagulant

Decreases fibrin formation and thrombin-induced plateletc aggregation

23
Q

Hirudin

A

From leecehs is a peptide inhibitor of thrombin

24
Q

Vitamin K dependant factors

A

Those that require a particular postranslational mdofication to be fully functional. This is the gamma-carboxylation of glutamate residues, enabling it to interact with Ca2+

These are factors:

II, VII, IX and X

25
Q

Factor VII

A

Zymogen –> enzyme (serine protease)

Activated to VIIa with TF and thrombin, X, IX and VIIa/Tf itself

With TF in complex, it activates F VII and IX respectively. Part of the extrinsic pathway.

action of the factor is impeded by tissue factor pathway inhibitor (TFPI), which is released almost immediately after initiation of coagulation

26
Q

Factor III

A

Tissue factor

Co-factor, not an enzyme

Transmembrane glycoprotein found on sub-endothelial tissues and in leukocytes.

Forms a complex with FVII to greatly increase its function

Seperated from FVII by endothelium

27
Q

Factor X

A
  • AKA stuart-prower factor
  • Zymogen
  • plasma glycoprotein
  • RKR tripeptide excised to form 2 chains (light + heavy)
  • Vitamin K dependant factor
  • Convergence point for both the intrinsic and extrinsic pathways
  • Once in a complex with FVa with Ca2+ and phosphopilkids on its surface can form the prothrombinase complex.
28
Q

Factor Xa

A
  • Active enzyme (serine endopeptidase)
  • Activated by actino of F VIIa or F IXa
  • Forms complex with FVa (+Ca2+ and PL) cleaving prothrombin to thrombin
  • Target for -xaban drugs
29
Q

Extrinsic pathway of coagulation

A

Activated by external trauma that causes blood to escape from the vascular system. This pathway is quicker than the intrinsic pathway. It involves factors VII, III, II, I and X.

Clinically measrued as prothrombin time

Shorter, activates the common pathway intially

30
Q

Factor Va

A

(proaccelerin)

Active co-factor

Plasma glycoprotein

Heavy chain and light chain helf together by Ca2+

Forms the prothrominase complex with FXa (+Ca2+ and PL)

31
Q

Rivaroxaban

A

Class; NOAC, direct Xa inhibitor

Chemistry; small molecule

Pharmacology; Target- FXa (prothrombinase complex) Activity-competitive inhibitor

Clinical; treatment/ prophylaxis of DVT and PE

32
Q

Common coagulation pathway

A

X–> Xa via the tenase complex

Tenase has two forms: extrinsic (F VII + tissue factor) and Ca2+

Or intrinsic- cofactor F VIII, F IXa, a phospholipid, and Ca2+.

Once activated to factor Xa, it goes on to activate prothrombin to thrombin.

F Xa requires FV as a cofactor to cleave prothrombin –> thrombin.

Thrombin goes on to activate fibrinogen –> fibrin.

Thrombin also goes on to activate other factors in the intrinsic pathway (factor XI) as well as cofactors V and VIII and factor XIII.

Fibrin subunits come together to form fibrin strands, and factor XIII acts on fibrin strands to form a fibrin mesh. This mesh helps to stabilize the platelet plug.

33
Q

Factor IXa

A

Intrinsic/ christmas factor

Prodcued as a zymogen –> Serine protease after cleavage by F XIa (of the contact pathway) or F VIIa (of TF pathway)

Deficiency causes haemophilia type B

In the presence of Ca2+, membrane phospholipids and co-factor FVIII, activates FX

Inhibited by antithrombin

34
Q

Intrinsic pathway

A

1) Exposed, damaged tissue (inc. collagen) activates F XII
2) Phosphatidylserine and F XIIa actiavte F XI
3) F XIa actiavtes F IX in the presence of Ca
4) F IXa and F VIII in the presence of Ca2+ and a phospholipid surface

actiavte F X

35
Q

In vitro anticoagulants

A

Blood samples clot easily

Chelatorsdecrease the amount of free Ca, disrupting F V, VIII, XII and vitamin K dependant factors

36
Q

Examples of in vitro coagulants

A

Citrate

EDTA

Heparin + unfractionated heparin

37
Q

Heparin aka unfractionated heparin

A

Glycosaminoglycan produced by the liver

Polymerised by disaccharide units

Highly sulphated polysaccharides

Strong negative charge

MoA: Binds to antithrombin, thereby activating it

38
Q

Low molecular weight heparin

A

Shorter strands of heparin that also act as an anticoagulant

e.g. dalteprin, tinzaprin

Fewer side effects

Derived from animals, not ok for vegans?

39
Q

Antithrombin- III

A

Serine protease inhibitor

Plasma glycoprotein

Inhibits thrombin, IXa, Xa, XIa

Activity greatly enhanced by heparin

bound to fondaparinux in complex with Xa

40
Q

Factor XIII

A

AKA fibrin-stabilizing factor

Activated by thrombin

Transglutaminase crosslinking glutamate and lysine in fibrin, polymerizing it and stabilizing it further. Clot retracts and hardens, closing the injury further

Ca and thrombin activate it

41
Q

Intrinsic tenase

A

made of IXa and its regulatory cofactor VIIIa

42
Q

Fibrinolysis

A

Fibrinogen–> firbin monomer–> fibrin polymer –>cross-linked fibrin polymer –> dissolution into FDPs

Carried out by plasmin (precursor plaminogen)

43
Q

Plasminogen

A

Zymogen –> plasmin

Activated by urokinase or tissue plasminogen actiavtor

44
Q

How are clotting factors removed?

A

When normal blood flow is restored, clotting factors are washed away

45
Q

Alteplase

A

Class: fibrinolytic

Chemistry: recombinant human tPA

Pharmacology: target- plasminogen activity- activator

Physiology- promotes endogenous fibrinolytic system and thrombus dissolution

Clinical: acute MI, PE

46
Q

Targets?

Dabigatran

Rivaroxaban

Heparin

Alteplase

A

F2

F10

antithrombin

synthetic tpa- fibrin

47
Q

Warfarin

A

MoA: Inhibits vitamin K metabolism and thereby the synthesis of several clotting factors, including prothrombin

Disrupts the posttranslatinal modification of all vit k dependant factors:

IX (intrinsich pathway)

VII (extrinsic)

X (common)

and F II (final)

48
Q

Citrates

A

Binds Ca 2+

49
Q

EDTA

A

Chelataes Ca2+ for in vitro coag

50
Q

Aspirin

A

Irreversibly inhibits the COX 1 and 2 enzymes so blocks the production of prostaglandins and thromboxanes, inc thromboxane A2 in platelets

Thus attentuates platelet aggregation and reduces the risk of arterial thrombosis.

51
Q

Haemophilia A, B and C

A

Haemophilia A- deficiency of VIII, X linked

B- IX, X linked

C-XI, autosomal recessive

52
Q

Intrinsic tenase

A

Fcator VIIIa +VIIIIa + Ca2+

53
Q

What does antithrombin inhibit

A

2a 9a 10a and 11a

54
Q

Fondaparineux

A

Synthetic type of heparin that binds and activates antithrombin

Unit 12 week 2 (Sam) (5 decks)

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