The coagulation system

Question 1

T or F: haemophilia is a genetic disease in which platelet function is impaired?

Answer 1

F, is a problem with factor 8 or 9

Question 2

Vit K deficiency at birth? risks?

Answer 2

severe bleeding in the brain

Question 3

Thrombosis definition

Answer 3

formation of an abnormal thrombus
vessel wall generally intact
Venous: red cells and fibrin
Arterial: platelet rich, occlusive

Question 4

Physiological haemostasis

Answer 4

BV wall disrupted
Form a thrombus to heal the defect
Platelet rich, generally size limited

Question 5

Haemostats breakdown

Answer 5

• Following vessel injury vessel vasoconstrictor
• Exposure of collagen in sub endothelial tissue
• Platelets adhered to collagen via circulating von-hillenbrand factor, binds platelet receptor GP1b to collagen
• Platelet morphology changes from disc to spiny sphere
• Shape change associated with release action involves the release of vasoconstricting amines (serotonin) and ADP –> further activation and aggregation
• Aggregation mediated by fibrinogen, binding platelets together via intergrin and alpha(IIb)beta(3) receptor which is activated during platelet shape change process
• Prostaglandin pathways in the platelet convert arachidonic acid to thromboxane A2 –> potent vasoconstrictor and aggregator

Question 6

purpose of the coagulation pathway

Answer 6

formation of fibrin (by activation of thrombin) around platelet plug to stabilise clot

Question 7

the 2 ways to activate the coagulation pathway

Answer 7

1. contact activation on a changed surface

2. protein tissue factor

Question 8

The coagulation pathway breakdown

Answer 8

Tissue factor - only expressed on sub endothelial tissues e.g. fibroblasts and smooth muscle - exposed following trauma
- Factor VII activated by binding to TF and trace amounts of other clotting factors
- VIIa, activates IX and X, this is rapid, this process is also rapidly inhibited by tissue factor pathway inhibiting factor (TFPI)
- Said initial burst of activation was to produce a small amount of Xa, then quickly stop it to prevent widespread coagulation
- Factor Xa slowly converts a small amount of prothrombin –> thrombin
Thrombin (amplifies coagulation pathway to produce more thrombin), activates V, VIII, XI, cofactors dramatically speed up coagulation
VIIa + IXa + calcium + phospholipid = tens complex
Tenase complex converts X to Xa
Xa + Va + calcium + phospholipid = prothrombinase complex
prothrombinase complex converts prothrombin to thrombin
Thrombin:
- Converts fibrinogen to fibrin
- XI –> XIa, which converts IX to IXa

Question 9

What is the modern theory of coagulation?

Answer 9

1. initial burst of factor VIIa activity with production small amounts Xa and thrombin
   Thrombin feedback activates factors V and VIII, accelerate thrombin generation, accelerate thrombin generation

Question 10

bonus of the role of phospholipids?

Answer 10

from endothelium of activated platelets keeps coagulation localised

Question 11

Fibrin clot formation

Answer 11

Fibrinogen composed of alpha, beta and gamma strands
Thrombin cleaves small fragments of alpha and beta chains so the chains can polymerise to long fibrin strands, stabilised by XIIIa (activated by thrombin)

Question 12

Other methods of coagulation

Answer 12

contact with negatively charges surface, little role in physiology but significant in APTT clotting test
When in glad tube factor XII spontaneously activates which i turn activates factors XI and IX (a good test for determining deficiencies of factors XII, XI, IX, and VII)

Question 13

What are the contact factors?

Answer 13

XII, XI, high molecular weight kininogen and prekallikerin

Question 14

What are the thrombin sensitive factors?

Answer 14

fibrinogen V, VIII and XIII

Question 15

What are the Vitamin K dependant factors

Answer 15

II, VII, IX,X have Gla domain, binds to phospholipid via an interaction with series of glutamic acid residues, need to be gamma carboxylated, which can only be done by Vit K, Vit K inhibited by warfarin,

Question 16

Natural inhibitors of coagulation

Answer 16

proteins prevent uncontrolled coagulation

• Antithrombin, inhibits thrombin also Xa, IXa, and XIa
• Protein C activated by thrombin (assisted by thrombomodulin)
• Protein S a cofactor of protein C

Question 17

Fibrinolytics

Answer 17

Activated when any clot forms, to digest clot
Fibrinolytic cascade, converts plasminogen –> plasmin
catalysed by tPA (tissue plasminogen activator) and uPA (urokinase like plasminogen activator)

Question 18

inhibitors of fibrinolysis

Answer 18

Antiplasmin binds to plasmin
Thrombin activates TAFI (thrombin activated fibrinolysis inhibitor), when thesis activated by thrombin, it removes lysine residues from fibrin, prevents plasminogen binding to the clot, inhibits fibrinolysis.

Question 19

vit K extra notes

Answer 19

Deficiency = bleeding 
get vit k from diet and bowel bacteria 
new born bleeding inside the brain associated with fit K deficiency and the trauma of birth = hemorrhagic disease of newborn 
vit K suplements at birth 
reversal of warfarin = 12 -24 hours

Question 20

Is contact activation important

Answer 20

Factor XII deficiency not associated with bleeding
Factor XI deficiency mild
Some mammals do not have factor XII

Question 21

Is the bleeding abnormal

Answer 21

start with a bleeding history 
- more important than lab test 
family history 
trauma / surgery - if didn't bleed a lot thats significant 
Menstruation 
Pregnancy 
Bruising or joint bleeds 
Epistaxis 
New borns: umbilical bleeding 
Bleeding in other sites