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

Blood coagulation Flashcards

(54 cards)

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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

Study These Flashcards
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

Study These Flashcards
A

From leecehs is a peptide inhibitor of thrombin

24
Q

Vitamin K dependant factors

Study These Flashcards
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
Factor VII
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
Factor III
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
Factor X
* 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
Factor Xa
* 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
Extrinsic pathway of coagulation
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
Factor Va
(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
Rivaroxaban
Class; NOAC, direct Xa inhibitor Chemistry; small molecule Pharmacology; Target- FXa (prothrombinase complex) Activity-competitive inhibitor Clinical; treatment/ prophylaxis of DVT and PE
32
Common coagulation pathway
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
Factor IXa
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
Intrinsic pathway
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
In vitro anticoagulants
Blood samples clot easily Chelatorsdecrease the amount of free Ca, disrupting F V, VIII, XII and vitamin K dependant factors
36
Examples of in vitro coagulants
Citrate EDTA Heparin + unfractionated heparin
37
Heparin aka unfractionated heparin
Glycosaminoglycan produced by the liver Polymerised by disaccharide units Highly sulphated polysaccharides Strong negative charge MoA: Binds to antithrombin, thereby activating it
38
Low molecular weight heparin
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
Antithrombin- III
Serine protease inhibitor Plasma glycoprotein Inhibits thrombin, IXa, Xa, XIa Activity greatly enhanced by heparin bound to fondaparinux in complex with Xa
40
Factor XIII
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
Intrinsic tenase
made of IXa and its regulatory cofactor VIIIa
42
Fibrinolysis
Fibrinogen--\> firbin monomer--\> fibrin polymer --\>cross-linked fibrin polymer --\> dissolution into FDPs Carried out by plasmin (precursor plaminogen)
43
Plasminogen
Zymogen --\> plasmin Activated by urokinase or tissue plasminogen actiavtor
44
How are clotting factors removed?
When normal blood flow is restored, clotting factors are washed away
45
Alteplase
Class: fibrinolytic Chemistry: recombinant human tPA Pharmacology: target- plasminogen activity- activator Physiology- promotes endogenous fibrinolytic system and thrombus dissolution Clinical: acute MI, PE
46
Targets? Dabigatran Rivaroxaban Heparin Alteplase
F2 F10 antithrombin synthetic tpa- fibrin
47
Warfarin
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
Citrates
Binds Ca 2+
49
EDTA
Chelataes Ca2+ for in vitro coag
50
Aspirin
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
Haemophilia A, B and C
Haemophilia A- deficiency of VIII, X linked B- IX, X linked C-XI, autosomal recessive
52
Intrinsic tenase
Fcator VIIIa +VIIIIa + Ca2+
53
What does antithrombin inhibit
2a 9a 10a and 11a
54
Fondaparineux
Synthetic type of heparin that binds and activates antithrombin

Unit 12 week 2 (Sam) (5 decks)

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