Disease State Overview

Thrombus

Thrombus (plural thrombi) is a blood clot that forms within a vessel and can cause obstruction of the blood flow.

Mature thrombi develop in three phases:

White thrombus: platelet plug; an aggregation of platelets only
Red thrombus: red blood cells become trapped in the fibrin mesh
Mature thrombus: platelets, red blood cells, and a meshwork of fibrin

How does thrombus form during PCI?

Thrombus is a complication of PCI. It occurs when atherosclerotic plaques are damaged, exposing prothrombotic substances to the blood. This can occur through either the spontaneous rupture of an atherosclerotic plaque (Fig. 1) or mechanical damage of a plaque during PCI (Fig. 2).

Figure 1. Spontaneous rupture of an atherosclerotic plaque.

Figure 2. Mechanical damage of the plaque during PCI

The damaged plaque exposes platelets in the bloodstream to collagen in the blood vessel wall. Collagen acts as a potent activator of platelets. When activated, platelets change shape from a smooth discoid shape to a spiculated (spiky) form (Fig. 3). This increases the surface area on which thrombin generation can occur and the GP IIb/IIIa receptor (integrin) is expressed.

Figure 3. Scanning electron micrographs of quiescent platelets (left) and activated platelets (right)

Activated platelets adhere to the damaged plaque (Fig. 4), release their granular contents (such as ADP and thrombin), and subsequently aggregate. This in turn recruits more platelets to the site of injury and increases the potential size of the thrombus.

Figure 4. Activated platelets adhere to the damaged plaque

The GP IIb/IIIa receptor is an integrin to which fibrinogen binds at both ends of the molecule, acting as a link between the GP IIb/IIIa receptors on differentiated activated platelets, enabling platelet aggregation and binding to endothelial cells and plaque (Fig. 5). Fibrinogen is converted to fibrin in the final part of the coagulation cascade, a process that is initiated by thrombin. Fibrin is an insoluble protein that forms a mesh-like network to stabilize the aggregated platelets into a stable thrombus.

Figure 5. Fibrinogen binding platelets via the GP IIb/IIIa receptor

Why is thrombus a problem?

Thrombus is present three times more often in angioscopy than is seen in angiograms (61% vs. 20%). The process of thrombus development is a dynamic one, involving a continual cycle of platelet aggregation and thrombus breakdown. However, thrombus generation can quickly spin out of control in the cath lab due to the mechanical damage caused by PCI propagate down the vessel. If a thrombus grows large enough, it can occlude the blood vessel completely. Swift treatment of such a blockage is essential, as it causes ischemia in the heart muscle. Prolonged ischemia can lead to myocardial necrosis (infarction), decreasing left ventricular function, and potentially lead to heart failure and death.

Embolization

Thrombus formation can also cause problems away from the initial site of vascular disruption. Clumps of aggregated platelets and thrombus may embolize and travel down the narrowing, bifurcating blood vessels into the microvasculature (Fig. 6). These small emboli become lodged in the microvessels, blocking the distal vasculature at the capillary bed, and preventing blood from passing.

Figure 6. Embolization

As with primary thrombi, this may produce ischemia, although to a more limited extent, with similarly damaging consequences for the patient. The potential challenge with thrombus emboli is a little different from thrombus that forms at the site of plaque rupture. The challenge here is that the distal beds can be blocked if there is a large enough shower of emboli downstream. This causes ischemia and can cause the angiographic phenomenon of “no reflow”. This causes blood upstream to take the path of least resistance down another artery and the area of tissue fed by the blood vessel with no reflow continues in its ischemic state. This can cause symptoms, electrocardiogram (EKG) changes, necrosis, and sometimes the patient becomes hemodynamically unstable.

Another possibility, and this is probably the most common circumstance, is that the many showers of emboli have gone downstream and the interventionalist is unaware of the situation because there are virtually no symptoms, the emboli are not visible, and the consequence of embolization is NOT to the procedure, but to the patient who may leave the cath lab with microvascular occlusion and elevated cardiac enzymes. These elevated enzymes are indicative of myocardial necrosis due to ischemia. Often, the interventionalist is unaware of elevated cardiac enzymes because they are not usually drawn post-procedure, and procedural success is usually defined visually at the end of the case.

Shear stress

The narrowing of the lumen of the vessel where plaque is present causes disturbances in local blood flow. This disruption of blood flow can be akin to whirlpools and eddies on the margins of a fast moving stream. These whirlpools and eddies of blood cause a lot of friction of blood cells on one another. This shear stress can activate platelets leading to platelet aggregation, and, therefore, exacerbate thrombus formation even further. Note that pharmacologic agents do not affect shear forces, but GP IIb/IIIa receptor inhibitors may affect the ability for platelets to aggregate in response to shear stress.

The limitations of devices in thrombus management

Percutaneous coronary intervention (PCI) using balloon angioplasty, usually in combination with stenting, is a widely used option for treating atherosclerotic vessels. Mechanical intervention is very effective in restoring immediate flow to the target vessel, but is associated with a number of limitations when it comes to the management of thrombus.

Balloon angioplasty and stenting

During angioplasty, the balloon is inflated to widen the artery at the area of obstruction in the vessel. This causes cracks to form in the plaque (Fig. 2), exposing collagen to blood flow and triggering thrombus formation. Expansion of the stent can abrade the plaque further, causing parts of the plaque to break off and flow downstream. Once the stent is positioned, thrombus can also form between the struts. Before the approval of ReoPro, interventional cardiologists in the early 1990s would try to use a balloon to open thrombus-occluded vessels, but this often met with limited success and may have exacerbated the situation.

With the risks of thrombus formation following PCI procedures and the inability of devices to reach all clots, there is a clear need for systemic pharmacologic therapies in the treatment and management of thrombotic conditions.