Millions of Americans are afflicted with peripheral vascular disease. Many of these suffer from insufficient blood flow to the legs resulting in pain and are commonly treated with a surgical procedure to bypass the diseased segment of artery. A common surgical procedure is the ‘fem pop’ bypass graft. Sometimes there are problems with this procedure. In approximately 7-10% of patients undergoing this procedure, the graft clots off shortly after the procedure. In essence, the blood supply to the leg goes from low flow to no flow and may ultimately result in loss of part of the leg.
The common approach to this problem is to give the patient an anticoagulant to prevent clotting. This seems rather simple. If the problem is clotting then give a drug that inhibits clotting. Notice the word ‘inhibits’. This is a double edged sword. The active ingredient in rat poison, for example, works by ‘inhibiting’ clot formation. Sure, clotting can be completely prevented with a high enough dose of anticoagulant, but death is the likely result. The task now becomes finding a dose that prevents the graft from clotting but that is low enough to avoid a major complication such as stroke or death. Sometimes this is a losing battle, hence the 7-10% rate of early clotting of the fem pop graft.
Perhaps it behooves us to employ a new line of thinking. It seems unlikely that the fem pop patient suddenly develops a deficiency of endogenous anticoagulants. Maybe we should try to figure out why the graft clots. Could it possibly be related to the nature of the operation itself? Might the ‘improved’ blood flow actually be not such an improvement? After all, the patient wasn’t clotting before the operation.
Let’s dissect the nature of the disease that leads to the operation. The patient has a disease that leads to a gradual narrowing of the arteries in his body. This is known as peripheral vascular disease. As the lumen of an artery progressively narrows, the ability to deliver blood to the tissue lessens, eventually to the extent it is unable to meet the metabolic demands of the tissue. In the case of the legs the point is eventually reached that upon walking, the increased need for oxygen is unmet by the limited capacity to deliver it via the decreased blood flow through the narrow diseased arteries.
It now seems simple enough.
Problem: Insufficient blood flow due to a narrowed artery.
Solution: Replace the narrowed artery with a bigger artery.
Sounds great! Most of the time it works. Unfortunately, some of the time the patients get worse. These unfortunate patients go from low flow to no flow. H-m-m-m? Not so good. The new vessel actually has blood clots form inside the lumen, plugging the lumen and preventing all flow.
Why does the operation lead to clot formation that did not occur before the operation? Let’s consider one possible cause of clot formation. Stasis. Blood tends to not clot when it is flowing and it tends to clot when it is not flowing. Stasis is a state of non-flow. Stasis begets clots. Clots beget stasis. Sort of sounds like a vicious cycle, doesn’t it? Well, maybe it is a ‘viscous’ cycle.
Allow me to take a moment to explain what is meant by this. Although the following proposal may at first seem counterintuitive, the subsequent discussion might explain how and why in such a fashion as to make it seem more reasonable. Possibly, in those patients that experience a failure of the fem pop procedure, the newly increased vessel lumen diameter is associated with an increase in the viscosity of the blood inside the new graft. This increased viscosity naturally leads to a drop in flow. The drop in flow results in an even greater viscosity which of course leads to a further drop in flow. It is clear that this is an unstable situation. The viscous vicious cycle continues until there is ultimately complete cessation of flow, otherwise known as ‘stasis’. In the absence of total anticoagulation, stasis results in clot formation.
This is an interesting conjecture, but do we have any reason to think that a newly widened vessel leads to an increased viscosity of the blood contained in it? Any plausible explanation should also explain why most of the patients don’t experience this vicious cycle.
The flow rate of any liquid through a tube depends on the pressure that drives the fluid flow and the resistance to the flow. For purposes of this discussion we shall make the reasonable assumption that the flow problem in these patients undergoing the fem pop bypass procedure is not due to a pressure problem, but rather to a problem with the resistance to flow.
So, what determines the resistance to flow? As demonstrated by Poiseuille, the resistance to flow of a liquid flowing through a tube of a fixed length is determined by the diameter of the tube and by the viscosity of the liquid. For the tube of a particular length and diameter with a given driving pressure, the flow goes up as the viscosity of the liquid goes down.
For water flowing through a tube, the matter is rather simple. For any given tube with laminar flow of fluid inside, if the tube is widened the flow is increased. It is simple because the viscosity stays the same regardless of what is done to the diameter of the tube. Want more flow? Then widen any or all of the tube. This intuitively obvious reasoning is problematic when applied to vascular surgery because, unlike water, the viscosity of blood may change with the diameter of the tube. As the diameter of the tube, or part of the tube, is increased the viscosity of the blood inside the tube (artery) may also increase. This increase in viscosity may be a little or it may be a lot. The net effect is that the diameter increase tends to make blood flow increase but the concomitant change in viscosity tends to make the flow decrease. Under the right set of circumstances, the good effect on flow might be outweighed by the bad effect on viscosity with a net reduction in flow. Compounding this, the drop in flow might lead to a further increase in viscosity and a further reduction in flow. Ergo – stasis and then clot.
Would you like any evidence of a liquid whose viscosity varies with its state of flow? Take a bottle of ketchup that has been sitting on a table for a while. Tip it so the ketchup is able to flow out. It doesn’t flow well at first but once the flow begins it flows readily. Fluids that behave such that the viscosity depends on the state of flow are called non-newtonian fluids. Ketchup is a non-newtonian fluid. Blood is a non-newtonian fluid.
If this explains why some patients get worse after a fem pop bypass graft, then it should make us wonder if there is any way to monitor the patients to show early on which are at risk of progressing down that slippery slope toward stasis and clotting. There is. The pertinent characteristics of flow though a vessel can be measured with ultrasound, as this provides both the vessel diameter and the peak velocity. The remaining required information for viscosity can be obtained with a sample of blood. The combined information can demonstrate whether or not the operation is causing the blood to enter the viscous vicious cycle and suggest the need to intervene.
This brings us to the final topic and final cause of this whole discussion. We wish to reverse the trend toward stasis and eventual clotting in those patients at risk of clotting off their newly enlarged vessels. This proposed solution involves the very composition of the blood that was sampled above to provide information on the viscosity. In essence, this boils down to the question ‘why is blood non-newtonian?’. Blood is non-newtonian in nature because of the manner in which the layers of flowing blood interact with each other as the layers slide (or shear) over each other in the process of flowing. The layers interact via an interaction between the red blood cells and the long proteins, specifically fibrinogen. At low shear rates, the fibrinogen forms bridges between red blood cells and it takes energy to break these bridges. At high shear rates, there is less opportunity for these bridges to form so less energy is required to break them. Thus, low shear rates imply high viscosity.
This leads us to the proposed treatment directed toward reversing the increasing viscosity associated with the new graft. Monitor the patient with ultrasound and blood sampling. If the viscosity is increasing, alter the relation between viscosity and shear rate by lowering the red blood cell concentration, the fibrinogen concentration, or both. The leg isn’t going to die from a lower red cell concentration, but it will die from no flow. The bottom line is that fem pop bypass grafts fail in some patients. Continued use of reasoning that treats non-newtonian blood in the same way as newtonian water is not yielding optimal results. Perhaps it is time to try a different form of thinking that recognizes the true nature of blood.