22 Coagulation Cascade FRCS Tr&Orth

Mr Quen Tang MBChB BSc FRCS Tr&Orth

It is very reasonable for your examiner to ask you about the mechanism of action of various anticoagulants used for thrombo prophylaxis in the frcs exam and for me to understand the mechanism of action or where they work i mapped out the coagulation cascade now many of your examiner’s won’t know the coagulation cascade in it and it can look quite impressive if

You can draw it out quite quickly and then mark on the various areas of the cascade where these antique regulations can work so first of all the coagulation cascade is a broadly divided into your intrinsic and extrinsic pathways now the extrinsic and intrinsic pathways sorry mister as the they they all come together to towards your common pathway and i’ll explain

Why that is later so first of all to start off with your intrinsic pathway you start off with factor 12 which is inactive it then gets converted into its active form which is denoted by a little a factor 12 a factor 12 a promotes the conversion of factor 11 to actor 11a and then this in itself promotes the conversion of factor 9 to back to 9a then this promotes

The conversion of factor 10 to factor 10 a and factor 10a promotes the conversion of pro thrombin to thrombin prothrombin is also known as factor 2 and thrombin known as factor 2a thrombin in turn promotes the conversion of fibrinogen to fibrin and fibrinogen is also known as factor 1 and fibrin is 1a now fibrin is essentially your fibrin clot and if if if if left

Alone you have endogenous products which would eventually degrade your fibrin into your fibrin degradation products and and you need plasmon for this so plasmon breaks fibrin down into your fibrin degradation products and in turn plasmon comes from plasminogen now coming up to your extrinsic pathway if you have damaged tissues you get a release of tissue factor so

This is from mechanical damage to tissues and your tissue factor itself promotes the conversion of factor 10 to factor 10a and therefore from the intrinsic pathway down here it continues into the common pathway so the common pathway starts from factor 10 onwards in addition to your tissue factor from your damaged tissues you have factor 7a which comes from factor

7 in your entry extrinsic pathway in addition from factor 9 to factor 10 a factor 8a here also helps promote along with factor 9a promotes a conversion of 10 to 10 a and of course this comes from factor 8 here and then from factor 10a which promotes prothrombin to thrombin is also aided by factor 5a which comes from factor 5 now there’s a there’s a there’s also a

Positive feedback loop in the coagulation cascade when it all kicks off this is your intrinsic this is your extrinsic when you get down to your thrombin thrombin itself has a positive feedback loop which works really at three places it positively feeds back to promote the conversion of factor 11 to 11 a here it also promotes the conversion of factor 8 to factor

8a and finally it promotes the conversion a factor 5 to factor 5a now this positive feedback loop as you can see kind of perpetuate their propagates and and amplifies the the cascade to the final product which is your fibrin clot now from here you can start talking about where particular antique regulations work anticoagulants work and the ones you need to know

About are heparin low molecular weight heparin possibly dabigatran and also tranexamic acid and and warfarin finally as well so before so let’s go to the heparins so heparin is actually a it actually potentiates the action of antithrombin 3 an anti thrombin 3 is endogenous and as the name suggests it’s normal role is to inhibit factor 10 and thrombin so that’s

That’s its usual role heparin promotes or initiates antithrombin 3 and by doing so it in turn in activates thrombin and factor 10 a or inhibits those two those two factors low molecular weight heparin is a direct inhibitor of factor 10a and works here another direct in inhibitor which is actually coming used as well a factor 10a is reaver aqsa ban so that that

Works here as well dabigatran is a is a direct inhibitor of thrombin as well so the big trend which is also licensed by the department of health x here and an tranexamic acid which is used in major trauma probably know a bit about the multi center crash to trial is an anti of fibrin ethic so a fibrin or lysis occurs by plasma which is from plasminogen and tranexamic

Acid inhibits the conversion of plasminogen to plasmin so you do not get your fibrin degradation product so you do not get fibrinolysis so you you you have more integrity to your fibrin clot so tranexamic acid works here by inhibiting the conversion of plasminogen to plasmin conversely the the medics thrombley people for massive pees and strokes and they often use

Tpa or streptokinase and incidentally that actually potentiates the conversion of plasminogen to plasmin and that’s how your thrombolysis asians work they work here so beyond that you now need to know how warfarin works now warfarin we know is an inhibitor of vitamin k but more specifically it actually inhibits vitamin k reductase now visitin k reductase is is an

Enzyme and it’s essential for the reduction of vitamin k to reduced vitamin k okay so so that actually helps vitamin k reductase helps this process of converting vitamin k to reduce vitamin k reduce vitamin k is a cofactor which is required for the gamma carboxylation of glutamic acid now glutamic acid so glutamic acid for carboxylation requires oxygen and carbon

Dioxide and this gamma carboxylation creates gamma carboxy glutamic acid and this is essential for clotting factors 2 7 9 and 10 so so this this process of vitamin k being reduced by vitamin k reductase reduce vitamin k is an essential cofactor for the gamma carboxylation of glutamic acid to gamma carboxy glutamic acid which is essential for the components of

Factors 2 7 9 and 10 once reduced vitamin k is used in this process it gets oxidized to oxidized vitamin k and again oxidized vitamin k is converted to vitamin k by vitamin k reductase here so warfarin itself is a direct inhibitor of this enzyme vitamin k reductase which in turn is essential through the gamma carboxylation of glutamic acid is essential for the

Components of factors 2 7 9 and 10 so on the coagulation cascade you can see that warfarin acts here an extrinsic pathway also acts here at the beginning of the common pathway and also acts here at factor 9 in the intrinsic pathway and finally at prothrombin as well which is factor 2 so acts here whorfin acts here as well so when patients particularly neck of femur

Patients when they come in with a long term warfarin and their inr is 3.5 and you rapidly want to get down we often give vitamin k to try to reverse the process of warfarin however as we know this can take quite a long time for the inr to finally come down and we commonly ask the hematologists on on a quicker reversal agent and they often suggest optiplex now octa

Plex is a prothrombin complex concentrate and essentially what it is it’s a really expensive product which contains clotting factors and specifically it contains clotting factors – 7 9 and 10 so it makes sense that optiplex contain these factors directly reverses the effects of warfarin by providing the factors that that vitamin k is essential to make in the first

Place so this is the clotting cascade and how it can be applied and and how various anticoagulants work which are commonly used in orthopedic surgery

Transcribed from video
22 Coagulation Cascade FRCS Tr&Orth By Quen Tang