There’s nothing like a wednesday morning of tutorials to make you realise all those things you once revised for exams are long lost in a thick and heavy mental fog (although thankfully not the same Fog that besieged a Californian fishing town and heralded the arrival of pirate ghosts with an incomprehensible interest in Jamie Lee Curtis back in 1980). Yesterday’s teaching schedule did nothing to disappoint on this score. By the end of two hours of teaching on haematology, I was pretty confident in my not knowing anything very much at all. I know I learnt it at some point. Well, maybe “learning” is overstating it- clearly I didn’t or I wouldn’t be writing this. Probably more likely I just looked at it. Either way, it seems no matter what I do there’s no recollecting the salient details of coagulation, and so rather than accepting this gaping deficit in my education I’ve decided to act before my knowledge debt hits a nadir of eurozone proportions. With that in mind, I put the two hour lunch break that I get in GP-Land to good use and revised the coagulation cascade.
THE COAGULATION CASCADE
The coagulation cascade is basically a series of steps whereby coagulation factors become activated in order to generate thrombin from its precursor, prothrombin, and fibrin from its precursor, fibrinogen, and make clots to stop bleeding. I’ve thought for a long time that the coagulation cascade was tremendously complicated, and I suppose it is until you really get your head around it. Wikipedia has a tremendous article on it HERE, but I’m going to try and simplify the whole thing down in to a coagulation nugget. The picture of the cascade on Wikipedia looks pretty terrifying. Especially when you start thinking about the “Intrinsic” (or contact activation) pathway, and the “Extrinsic” (or Tissue Factor) pathway. But fear not! I’ve stripped the whole thing right down to the basics (thanks to Kumar and Clark).
Coagulation is INITIATED BY TISSUE INJURY, which exposes Tissue Factor (TF). Tissue Factor binds and activates Factor VII (VIIa). The Factor VII/TF complex then goes on to activate Factor X, as well as some Factor IX.
In the presence of activated Factor X (Xa), Tissue Factor Pathway Inhibitor (TFPI) inhibits further generation of Xa and IXa (see the RED ARROWS on the above picture). The extrinsic pathway therefore stops making activated Factor X (Xa) and IXa. But by this stage of the cascade, there isn’t sufficient Xa to fuel complete coagulation, and so extra Xa is needed to complete haemostasis.
The extra Factor Xa is generated by an alternate route, and is made by Factor VIIIa and IXa in the INTRINSIC pathway. Enough thrombin has now been generated to activate Factor VIII (as well as Factor V), and this activated Factor VIII as well as activated Factor IX (which itself is made by the VIIa/TF complex) can be utilised in the intrinsic pathway to generate further Xa and drive haemostasis to completion.
Activated Factor V (Va) drives the conversion of Prothrombin to Thrombin. Thrombin then hydrolyses the peptide bonds of fibrinogen and causes its conversion to fibrin. Thrombin (along with Ca2+ ions) also activates factor VIII, which itself works to stabilise fibrin clots by cross-linking neighbouring fibrin molecules.
So that’s the coagulation cascade (or the especially important steps, anyway). Of course, in reality there are many more coagulation factors involved, all of which work to activate one another to drive haemostasis.
Some other important details- Factor VIII helps to increase Factor IX activity (by around 200,000 times, according to Kumar and Clark). Factor VIII is also associated with Von Willebrand Factor, VWF (which itself is abnormal in Von Willebrand’s Disease). VWF helps stop early breakdown of Factor VIII, and binds to areas of injury to recruit Factor VIII to initiate clot formation.
BLOOD TESTS TO INVESTIGATE CLOTTING
PROTHROMBIN TIME (PT)
Normal range 12-16 seconds. This measures the EXTRINSIC pathway (eg. Factors VII, X, V, Prothrombin, Fibrinogen). It is prolonged in patients with deficiencies in these factors. INR (International Normalised Ratio), used to assess patients on warfarin, is based on this.
ACTIVATED PARTIAL THROMBOPLASTIN TIME (aPTT)
Normal range 30-50 seconds. This measures the INTRINSIC pathway (eg. Factors V, VIII, IX, X, XI, XII, Prothrombin, Fibrinogen). It is prolonged in patients with deficiencies in these factors. It is NOT Factor VII dependent.
THROMBIN TIME (TT)
Normal range 12-14 seconds. Assesses a patient’s ability to produce fibrin (by adding thrombin to a blood sample). It is prolonged in those with fibrinogen deficiency, defects in fibrinogen, or in those on heparin.
WHAT STOPS COAGULATION?
We’ve gone through the key players in coagulation, but there must be some mechanism for the body to stop coagulation. There are three major proteins that are involved in limiting coagulation, and they act at different points in the coagulation cascade to inhibit it.
This is a serine protease inhibitor and a strong inhibitor of coagulation. It inactivates serine proteases by forming stable complexes with them. Its action is enhanced by heparin.
ACTIVATED PROTEIN C
This is generated by its precursor (which is vitamin K dependent) by thrombin. Thrombin activation of Protein C is increased by thrombomodulin on endothelial cells. It inactivates factors V, VIII to decrease further thrombin generation.
This is a co-factor for protein C, which acts by enhancing binding of activated protein C to the phospholipid surface of cells. 30-40% is unbound and active in the blood, the remainder is bound to the C4b binding protein.