Primary hemostasis - Part 1 Welcome to the topic hemostasis. In this series
of Chalk Talk episodes, we’ll present the physiology of hemostasis, but we’ll also
go one step further and provide links to the most important conditions and drugs. Before
we delve into the details, let’s take a look at the big picture:
Thrombi can form in the arterial and venous system; however, there are differences in
drugs used in the prophylactic treatment of thrombi. The key message that we’d like
to deliver is the following: In atherosclerotic diseases, platelets play
an important role in initiating coagulation. Arterial thrombosis can, therefore, be prevented
using antiplatelet drugs such as aspirin. Platelets are also present in the venous system;
however, they play a minor role. The predominant feature of the venous system is the relatively
slow blood flow rate, which poses a risk to spontaneous fibrin thrombus formation. Therefore,
venous thrombosis is best treated using anticoagulants such as coumarin.
Let’s start with a concise overview of hemostasis. Hemostasis can be differentiated into primary
hemostasis and secondary hemostasis. The aim of primary hemostasis is to stop bleeding,
which is achieved by platelet aggregation in vascular lesions. A thrombus termed white
thrombus is formed due to the absence of red blood cells.
The thrombus is at risk of detaching and is stabilized by secondary hemostasis. In secondary
hemostasis, coagulation factors are activated leading to the formation of fibrin strands,
which strengthen the thrombus. Because red blood cells become trapped in the fibrin strands,
the thrombus is termed red thrombus. Secondary hemostasis is also called coagulation.
Coagulation is followed by fibrinolysis. Fibrinolysis dissolves blood clots and initiates wound
healing. Let’s start with a close look at the first
step of hemostasis, primary hemostasis. Primary hemostasis can be divided into vascular
and platelet hemostasis. After vascular injury, smooth muscle contraction
occurs within seconds in the vicinity of the lesion. Muscle contraction appears to be a
reflex in response to smooth muscle stimulation. However, this process is not completely understood.
The initial contraction of blood vessels lasts for approximately 60 seconds and is facilitated
by substances released from platelets. Vasoconstriction directly reduces blood loss
through decreased vessel injury and redirection of blood flow.
In addition to reducing blood loss, vascular hemostasis has a second important function.
Vasoconstriction creates increased shear stress in vessels. Shear stress is a term used in
physics. Let’s use an example for illustrative purposes: Shear stress occurs between two
areas displaced parallel to one another. But where does shear stress occur in blood?
Let’s imagine a laminar flow, where blood flow is faster in the middle of the vessel
than at the vessel wall. Shear stress is generated between these layers with different flow rates.
Shear stress is greatest at the external vessel wall as a result of friction and decreases
towards the middle of the vessel. So why is this relevant for hemostasis? The
distribution of cells in blood vessels varies in accordance with shear stress. Large cells,
such as red blood cells and leukocytes, tend to flow towards the middle of the vessel to
avoid shear stress at the vessel wall. In contrast, the smaller platelets are forced
towards the vessel walls, which favor platelet aggregation at the site of vessel injury.
This is the second major effect occurring in vascular hemostasis.
Let’s briefly summarize the most important aspects of vascular hemostasis. After vessel
injury, vasoconstriction occurs, which reduces blood loss and increases shear stress. Shear
stress facilitates the accumulation of a large number of platelets. As we’ll see in the
next section, platelets adhere to vascular lesions especially under high shear stress.
Platelet hemostasis aims to seal the vascular lesion and stop bleeding. The first step begins
with platelet adhesion. In intact blood vessels, platelets are separated
from the endothelium by subendothelial connective tissue. If the endothelium becomes damaged,
collagen fibers are released and platelets accumulate. For this to occur, platelets require
von Willebrand factor, or, in short, vWF, as shown in the image.
Von Willebrand factor is formed in endothelial cells independent of vascular injury and is
secreted into the blood. If there is vascular injury, von Willebrand factor binds to collagen
fibers. Platelets have a receptor for von Willebrand factor, abbreviated here as vWR,
through which they bind to von Willebrand factor. This process is termed platelet adhesion
and is the basis for the next phase, platelet activation. Details on platelet activation
will be discussed in the next episode. But before that, let’s briefly review a few
relevant conditions: The first condition is von Willebrand disease,
the most common hereditary coagulation disorder. Von Willebrand disease is caused by a defect
or deficiency in von Willebrand factor, resulting in impaired platelet adhesion and bleeding
tendency. There are three types, each presenting with a different degree of bleeding tendency.
Further information on von Willebrand disease can be found in its respective chapter via
the link. In thrombotic thrombocytopenia purpura, or
TTP, there is a pathological increase in platelet adhesion. We previously mentioned that von
Willebrand factor is formed in endothelial cells. However, we withheld one aspect concerning
its physiology. Von Willebrand factor is a large molecule
present in plasma and it is cleaved by a protease into smaller subunits. This protease is termed
Adam-T-S-13. The activity of von Willebrand factor is regulated by this process and prevents
premature platelet aggregation in the blood vessel.
TTP is caused by decreased Adam-T-S13 activity, which is mainly due to autoantibodies. When
protease activity in blood is decreased to levels below 10%, this results in an increased
length of von Willebrand molecules on which platelets adhere, leading to thrombus formation.
Because many platelets are used in the process, patients usually have thrombocytopenia, which
is associated with a bleeding tendency. This combined bleeding and clotting tendency also
explains why the term thrombotic thrombocytopenia purpura is used.
Let’s move on to the third and final condition that we’d like to present: thrombocytopenia.
A healthy individual has approximately 150,000 to 400,000 platelets per microliter of blood.
If the platelet count falls below 150.000 per microliter, this condition is termed thrombocytopenia.
Primary hemostasis disorders can result from thrombocytopenia.
However, even with significantly fewer platelets, platelet hemostasis remains functional and
can prevent spontaneous bleeding.
OK, so let’s briefly summarize the three
platelet adhesion disorders just mentioned. A dysfunction of von Willebrand factor and
a deficiency in platelet numbers can lead to reduced platelet adhesion. A dysfunction
of the protease ADAM-T-S-13 increases platelet adhesion, resulting in thrombus formation
inside blood vessels.