Primary hemostasis - Part 2 In the previous episode, we looked at platelet
adhesion. In this episode, we will focus on platelet activation.
Platelet activation is initiated by the binding of platelets to von Willebrand factor. This
binding causes platelets to change shape. Platelets lose their flat, discoid shape and
form thin projections, enabling improved interaction with the wound as well as to each other. These
projections can be rather long, as shown in this figure. To provide an overview, the projections
are schematically shown here. Platelet adhesion also results in the release
of chemical messengers stored in platelets. A very important chemical messenger is adenosine
diphosphate, in short ADP. Platelets have an ADP receptor from which additional inactive
platelets become activated. This results in positive feedback, which initiates a chain
reaction of platelet activation. A second chemical messenger released from
platelets is thromboxane A2, or TXA2. Thromboxane A2 has two important functions. It acts on
the blood vessel wall and strengthens vasoconstriction. Thromboxane A2 also activates additional platelets,
which seal off the site of injury. From a pharmacological perspective, thromboxane A2
is synthesized by cyclooxygenase 1 in platelets. But let’s get back to that later on in this
episode. As an important last step, activation causes
platelets to connect to one another, also termed platelet aggregation. The receptor
glycoprotein IIb/IIIa, in short GPIIb/IIIa, is present on the platelet surface.
Platelet activation results in a conformational change of the receptor glycoprotein IIb/IIIa
to enable binding of fibrinogen to the activated platelet. Platelets are then crosslinked and
an aggregate is formed that is somewhat unstable. The most common receptor present on the platelet
surface is glycoprotein IIb/IIIa, with more than 50,000 copies per platelet.
Up to now, we’ve presented the most important aspects of platelet hemostasis.
Let’s briefly summarize these aspects. Platelet hemostasis starts with adhesion that
is mediated by von Willebrand factor. As a result, platelets are activated and release
ADP and thromboxane A2, which furthers platelet activation. Platelets are subsequently connected
to one another, a process termed aggregation. During this process the fibrinogen receptor:
glycoprotein IIb/IIIa plays a central role. Up until this stage, the thrombus formed mainly
contains platelets, but not red blood cells. Therefore, it is also termed white thrombus.
At this stage, it would be ideal to link the fundamental aspects of hemostasis with the
mechanism of drug action. Let’s look at antiplatelet drugs, which include acetylsalicylic
acid, commonly known as aspirin, and clopidogrel. In platelets, aspirin inhibits the enzyme
cyclooxygenase 1. Inhibition of cyclooxygenase 1 is irreversible and continues regardless
of whether aspirin levels in plasma decrease again. This effect differs in nonsteroidal
antirheumatic drugs such as ibuprofen, with reversible binding of ibuprofen to cyclooxygenase
1. Therefore, the effect on platelet aggregation depends on plasma levels and is absent after
an average of 24 to 48 hours. An important point can be derived from the
different mechanisms of action. If a patient takes both ibuprofen and aspirin, cyclooxygenase
1 is only partially reversibly inhibited by ibuprofen. The effect of this inhibition is
gradually restored, resulting in a lack of inhibition of platelet aggregation. At least
95% inhibition of platelet cyclooxygenase 1 is required for a cardioprotective effect.
Therefore, one current recommendation is to take aspirin 30 minutes before ibuprofen or
if the patient has already ingested ibuprofen, aspirin should not be taken until at least
after 8 hours. The second drug that we’ll be discussing
is clopidogrel. Clopidogrel is an ADP receptor inhibitor. As the name suggests, it acts by
blocking the ADP receptor, preventing platelet activation. Because of the irreversible blockade,
the duration of action of aspirin and clopidogrel is similar to that of the platelet lifespan.
This corresponds to approximately 7 days after discontinuation and should be considered when
scheduling large-scale surgeries. Finally, let’s look at glycoprotein IIb/IIIa
inhibitors. They can be used in, for example, acute coronary syndrome. An example of a glycoprotein
IIb/IIIa inhibitor is tirofiban. It prevents fibrinogen binding and cross-linkage between
adjacent platelets. Therefore, tirofiban inhibits platelet aggregation
independent of an activating stimulus and is used in addition to other antiplatelet
drugs. In contrast to aspirin and clopidogrel, glycoprotein IIb/IIIa inhibitors can only
be administered intravenously. They are reserved for inpatient treatment, whereas aspirin and
clopidogrel can also be used as a long-term prophylaxis against thrombosis.
If you would like further information on these drugs, just click on the link for the respective
chapter. As we’ve just seen, antiplatelet drugs can
be used for preventing arterial thrombi and for treating acute coronary syndrome. This
brings us back to the initial question raised in the first episode concerning the preferred
drug prophylaxis based on the type of thrombosis. Vascular conditions differ between the arterial
and venous systems. The arterial system is characterized by high flow velocity. Platelets
are, therefore, of particular importance, because they are able to adhere to the site
of injury via their receptors. On a pathophysiological level, this ability can induce a negative
effect. In stenosis, flow velocity increases as a
result of constriction. Laminar flow is disrupted resulting in turbulent flow. At this stage,
shear forces are much higher than that in the normal vascular system. If a plaque ruptures,
platelets aggregate and form a thrombus, which can lead to vessel stenosis.
Therefore, drugs that inhibit platelet function are very important in preventing thromboembolic
complications in the arterial system. In contrast, the venous system is under different
physiological conditions. To describe these, let’s jump ahead a little. Platelet hemostasis
is followed by coagulation. In other words, coagulation factors surrounding the platelets
are consumed and fibrin is deposited, which strengthens the thrombus.
We’ll take a look at the details of coagulation in the next episode. For now, it’s important
to note that coagulation doesn’t switch from an off state to an on state. In fact,
even in the absence of injury, there is a continuous turnover of coagulation factors,
which significantly increase in vascular injury. Under certain conditions, especially in slower
blood flow, a fibrin clot can also form in the vessel without vascular injury.
This problem is less pronounced in the arterial system, where there is high flow velocity
that counteracts spontaneous fibrin clot formation. The venous system, however, is defined by
low flow velocity, in which coagulation factors can accumulate, especially in venous congestion,
for example, in the leg veins on long-haul flights. This means that the regulation of
coagulation is the first priority of the venous system.
To prevent thrombosis in the venous system, antiplatelet drugs are not the drugs of choice.
Instead, drugs that affect coagulation are used. These are termed anticoagulants.
Finally, just a small note to avoid confusion. The link between arterial thrombosis prophylaxis
and antiplatelet drugs, and venous thrombosis prophylaxis and anticoagulants is correct;
however, it doesn’t represent the whole picture.
Because platelet hemostasis is followed by coagulation, it’s also reasonable to administer
an anticoagulant, at least for the treatment of arterial thrombosis, such as in acute coronary
syndrome. In this case, heparin is usually administered.