Haemostasis and the Clotting Cascade Flashcards
What is the Virchow Triad?
Named in honour of the ‘father of modern pathology’, Rudolf Virchow, this describes the three broad categories of factors that affect thrombosis (AKA blood coagulation, clotting). These are;
• Stasis (Blood Flow)
o The variation in haemodynamic forces, interruptions due to venous stasis/DVT, extended surgery, pressure, flow restriction.
• Endothelial injury (Blood Vessels)
o Damage and piercings arising from shear stress, turbulent flow, infection and damaging agents such as glycated proteins, ox-LDLs, free radicals.
• Hypercoagulability (Blood Contents)
o Ease of clotting of the blood depends on its contents, the levels of various coagulation factors, platelets and cells. This, as well as extrinsic damage due to nephrotic syndrome or burns, can alter viscosity and coagulation potential.
Several links obviously exist between all of these parts of the triad, with a lot of interplay between the components involved.
How does the endothelium prevent clotting?
• Production of Prostaglandin E2 and Prostacyclin
o These are factors that counteract platelet activation, whose activity is increased by the endothelium’s production of nitric oxide.
• Production of CD39 and CD73 ectonucleases
o These convert ATP and ADP (pro-thrombotic) to adenosine (anti-thrombotic).
• Surface bound factors
o Proteoglycans such as heparan on in the inner lining prevent adhesion of platelets to the vessel, and activate antithrombin.
o Thrombomodulin and endothelial protein C receptors participate in coagulation inhibition pathways.
• Production of Tissue Plasminogen Activator
o Acute mechanisms of regulation of secretion allows local concentration to adapt to prevent nearby thrombus formation.
What is the clotting cascade made of?
This takes the form of a series of serpins cleaving the next factor in the cascade in order to activate it.
How can the clotting cascade be activated?
It is activated by two separate pathways (the intrinsic and extrinsic), which both feed into a common pathway at clotting factor X, both cleaving it to produce Xa.
What is the first step in the common pathway?
X is cleaved into Xa
Xa forms the prothrombinase complex with Va, which rapidly cleaves prothrombin (II) into thrombin (IIa), which in turn cleaved fibrinogen (I) into fibrin (Ia), allowing for production of a fibrin-crosslinked clot.
What is the prothrombinase complex?
This is a complex of Xa and Va with a ligated calcium ion, that forms bound to the surface of a platelet. All of these factors are required for to give Xa the required catalytic activity, with Va acting as a cofactor that increases the catalytic efficiency 1000x.
How does the intrinsic pathway begin and feed into the common pathway?
This is activated by the exposure of negative surfaces such as collagen (as occurs during endothelial breach), which catalyses the conversion of XII to XIIa.
XIIa converts XI to XIa, which converts IX to IXa. IXa forms the tenase complex with activated VIII, and feeds into the common pathway by converting X to Xa.
What is the tenase complex?
This is the active complex of IXa and VIIIa, which binds a calcium ion and docks onto the surface of the platelet. The complex can form without VIIIa, but is very inefficient as VIIIa is needed to increase its rate 100,000 fold to 10^9.
How is the extrinsic pathway activated and how does it feed into the common pathway?
This pathway consists of only clotting factor VII, which is cleaved into VIIa in response to the presence of tissue factor, which is recruited to sites of endothelial damage.
Once activated, VIIa performs the same role as IXa, feeding into the common pathway by converting X to Xa.
How is the clotting response measured?
Bleeding time tests are used as diagnostic tools to evaluate the capability of the patient’s coagulation response, a crucial thing to note for surgical procedures. Two different protocols exist which test the speed of each pathway, comparison of which can indicate where in the cascade the error may be causing altered coagulative capacity.
The Activated Partial Thromboplastin Time (APPT) test measures the speed of the intrinsic pathway, while the Prothrombin Time (PT) test measures the speed of the extrinsic pathway.
Why must the clotting cascade be carefully regulated?
In order to clot quickly, but not be prone to dangerous thrombi, the clotting cascade must be carefully regulated.
Many of the mechanisms surround thrombin, making it a key regulatory element.
Why must thrombin propagate the clotting cascade?
Itself a product of the cascade within the common pathway, thrombin also acts upstream to prolong the cascade for long enough to produce a thrombus.
How does thrombin propagate the clotting cascade?
It does this by upregulating Factors Va and VIIIa (by releasing it from its protective complex with vWF), cofactors involved in the common and intrinsic pathways respectively, as well as stimulating XI and hence the intrinsic pathway some more.
Thrombin is even capable of cleaving its own precursor – prothrombin, to make more of itself.
How is the clotting cascade terminated by extrinsic factors?
Two of the three termination mechanisms are extrinsic, with TFPI inhibiting VII (the cofactor that stimulates IX and X) and antithrombin directly inhibiting thrombin and the Xa/Va complex. These are triggered by various external factors.
How is the clotting cascade terminated by intrinsic factors?
Thrombin also negatively regulates its own levels, adding an intrinsic negative feedback loop.
This is facilitated by its activation of Protein C (PC) to activated protein C (APC), which degrades factors V and VII – the same ones upregulated by thrombin.
Thus thrombin ensures its concentration in the blood remains steady.
What is tissue factor?
This is produced in response to blood vessel damage, or in response to inflammation, activating the extrinsic pathway as well as the intrinsic one.
It is found as a surface membrane bound protein in a particular set of cells.
Which cells express tissue factor as a surface protein?
• Adventitial cells (sub-endothelial cells) • Keratinocytes • Epithelial cells o Mucous membranes o Organ capsules
- Renal Glomeruli
- Brain cells
