When I am consenting a family for extracorporeal membrane oxygenation (ECMO) and discussing the risks and benefits to initiating support, bleeding and clotting are the most common risks that are brought up, second only to the procedure itself. When we consider ECMO for patients, we are weighing the benefits against the risks, chief of which are bleeding and thrombosis.
This is not surprising. Bleeding is the most common complication reported in ECMO, occurring in as many as half of all cases, with clotting/thrombosis not far behind, occurring in a quarter to a third of all cases. While bleeding/thrombosis are common, we can equip ourselves with a much better ability to manage and mitigate these complications by developing an understanding of the mechanisms by which we are able to anticoagulate the blood and how those lead to bleeding in patients on ECMO.
Why do we need to anticoagulate in ECMO?
Normally, blood is pumped from the heart, through a continuous network of blood vessels all comprised of tissue that the body and immune system recognizes. So what happens when blood is pumped through the ECMO circuit? Consider the differences:
It is sucked through a negative venous drainage cannula.
It takes large and small turns introducing turbulence.
It is exposed to a motor turning at 1500–10,000 revolutions per minute with shear stress.
It is exposed to a host of plastics and other foreign substances, which activate the immune and complement systems.
It is cooled when it goes out of the body and rewarmed by the water from the heater cooler.
The take-home point being that there is nothing natural or normal about extracorporeal blood flow. The result is that the blood flowing from the extracorporeal circuit has a higher likelihood of being inflamed and is more likely to clot. Hopefully as the technology for circuits/pumps continues to improve, this trauma and inflammatory activation of blood will be minimized. However, in the interim, the solution is management of the thrombosis effect through anticoagulation.
Understanding the principles behind hemostasis
Many practitioners struggle with anticoagulation and bleeding management with good reason – the way the body forms and breaks down clot is a dynamic and complex system. That said, there are some principles that we can establish which hopefully will give a framework for approaching the management of anticoagulation on ECMO. The best way to build this framework is to start by examining how bleeding is stopped by the body on a basic level. Let’s review.
Let’s say you are preparing dinner – and tonight is kebab night! However, as you are slicing the peppers, your mind drifts and you accidentally cut your finger. As you rush to hold pressure, your mind again drifts to imagining how your body can stop this bleeding.
Bleeding is occurring in this case due to the disruption in the integrity of the blood vessel due to a brutally sharp kitchen knife ( Fig. 20.1 ).
At a basic level, your body is able to stop the bleeding through two mechanisms: creation of an initial web/scaffolding (fibrin) and adherence of cells to plug the hole (platelets). Clearly, both elements are necessary – without the web, the platelets would have nothing to adhere to, and without the platelets, there would be no integrity to whatever initial scaffolding is laid down ( Fig. 20.2 ).
The clot then can become stronger as it progresses from three phases:
- 1.
Initiation: Initial mesh generation at the site of injury
- 2.
Propagation: Platelet adhesion to the fibrin mesh, activation of factors needed to solidify fibrin mesh
- 3.
Amplification: Platelets aggregating to each other with fibrin mesh maturation
You can quickly imagine why this requires a dynamic process – you need to form clot when there is bleeding and not form clot when there is no bleeding. Any breakdown in the system can lead to excessive thrombosis or excessive bleeding. The body is able to regulate this through the coagulation cascade.
The coagulation cascade: How clotting is regulated
There are many factors that go into the coagulation cascade, so let’s break things down into smaller steps. Ideally, you want to accomplish the following steps:
Step 1: Form clot where there is bleeding
Step 2: Lay down initial framework for clot
Step 3: Activate platelets to form the plug
Step 4: Form enough clot to stop bleeding
Step 5: Stop clotting when bleeding stops
Step 6: Break down clot
Let’s break down each step and the factors that go into each.
Step 1: Form Clot Where There Is Bleeding
You need the initiation of this cascade to be specific to the spot where there is bleeding. Otherwise, clotting can occur anywhere, and would not focus on places where the integrity of the blood vessel has been disrupted, like our unfortunate lacerated finger, for example.
The way this happens is that the blood vessel that is damaged releases tissue factor. This combines and activates factor VII. You may recognize activated factor VII, as this is what is sometimes administered in severely bleeding patients. This is one of the reasons it is administered – it is the initial entrance point into the coagulation cascade ( Fig. 20.3 ).
Step 2: Lay Down Initial Framework for Clot
Remember that the scaffolding of our clot is fibrin mesh – it is what the platelets adhere to. The cascade that activates fibrin and allows for this fibrin mesh generation is initiated by the activated factor VII/tissue factor complex. This does not happen directly but rather happens through the activation of other factors: tissue factor/factor VIIa activates factor X , which activates thrombin , which activates fibrinogen ( Fig. 20.4 ) .
Why all these steps? Every extra step represents a point where the cascade can be regulated, which is a good thing. An unregulated system ultimately leads to a disorder of bleeding or clotting. Rather, this becomes a delicately arranged symphony, allowing for the perfect balance. Pay attention to the factors mentioned; they are not arbitrary and will ultimately play a specific role in how we manage our patients.
Step 3: Activate Platelets to Form the Plug
Now that we are done with step 2, we have our scaffolding started and are ready to start to form the plug! Remember, our plug is made of platelets.
Platelets need to be activated by our cascade so that they are ready to adhere to the fibrin mesh only when there is bleeding. Ideally, the factor that activates these platelets would be downstream of the cascade, capturing the feedback of the entire cascade, without being the end product of the cascade. That is exactly what happens with thrombin, our second to last factor that activates platelets! Pay attention to thrombin, this is not the last time it will play a role in our clotting cascade ( Fig. 20.5 ).
Step 4: Form Enough Clot to Stop Bleeding
Now we have our scaffolding (fibrin mesh) set up at the site of bleeding and have started to plug the hole with platelets. All that is left to do is to ramp up the system, increasing the activation of platelets and the generation of fibrin mesh.
Doing this employs another cascade of factors that is intrinsic to the body, rather than extrinsically activated (by tissue factor), and therefore is designated as the intrinsic cascade. The steps of the intrinsic cascade (factor IX activating factor XI, which activates factor X) are less relevant to our discussion but what is important is the factor that activated it. You guessed it – our friend thrombin ( Fig. 20.6 )!
We should pause here and reflect on how thrombin is the lynch pin of this whole process in many ways – this one factor activates our platelets, contributes to the fibrin mesh generation as the precursor to fibrin, and ramps up the system by activating the intrinsic cascade. We will revisit the essential role of thrombin as it plays a key role the regulation of this cascade.
Step 5: Stop Clotting When Bleeding Stops
Congratulations, you now have a strong clot with both activated platelets and a mature fibrin mesh right where you need it, at the site of the injury. You can now release pressure on your bleeding finger and it will not continue bleeding. But the process is not over here. Much like a full bathtub requires that you must turn off the water, the next step is turning off this process. If the system did not have this step, then clotting would continue and excessive thrombosis would ensue ( Fig. 20.7 ).
The system to inhibit clotting is as complex as the system to lay down the clot, with many proteins and enzymes inhibiting factors at different points in the cascade, protein C, protein S, tissue factor pathway inhibitor, and antithrombin to name a few. Subtlety is the name of the game here – multiple enzymes allow for nuance in how the system is broken down.
Step 6: Break Down Clot
Finally, once the tissue is repaired, there must be a system to actually break down the clot/fibrin mesh. This is different than Step 5 – it is draining the bathtub rather than simply turning the water off, to use our analogy. The process of breaking down our fibrin mesh is referred to as fibrinolysis, and is facilitated by the activation of plasminogen to plasmin, which in turn breaks down the fibrin mesh ( Fig. 20.8 ).
