Secondary hemostasis - Part one
Welcome to this Chalk Talk episode on hemostasis.
You’ve probably sat down in front of the coagulation cascade and asked yourself: “How
am I going to remember all of these factors?!” Adding to the complexity, textbooks usually
cover the details of coagulation in a laboratory setting and hardly describe the sequence in
an injured blood vessel. In this Chalk Talk episode, we'll introduce you to coagulation.
In the second part, we'll present the cell-based model of coagulation. So, let’s get started!
In the previous episodes, we’ve learned that primary hemostasis results in the formation
of a loose thrombus, also termed a platelet plug. The platelet plug is then stabilized
by the coagulation cascade of secondary hemostasis. This is achieved by cross-linking the fibrin
network to the platelet plug, a process driven by clotting factors.
The classical coagulation cascade can proceed via two pathways that merge into a joint pathway.
This division is for historical reasons. Hippocrates identified that bleeding from a wound can
be rapidly stopped if the wound is covered with skin. He came to the conclusion that
there must be specific factors present in tissue that stop bleeding. Then, over 2000
years later, blood was shown to coagulate when added to a glass tube. Because coagulation
appeared to be initiated without the addition of any external factors, two different pathways
were defined: the intrinsic pathway and the extrinsic pathway. The respective clotting
factors involved were subsequently identified and placed in a sequence of reactions. This
is how the cascade model was developed and was first proposed in the 1960s. It’s comprised
of two arms that converge to form the final common pathway. This structure has proven
especially useful in understanding coagulation tests. However, for explaining the coagulation
process in the body, the cascade model is less suitable.
Let’s look at an example. Hemophilia A is a bleeding disorder caused by deficiency in
factor eight, which plays a role in the intrinsic pathway. Because the extrinsic pathway of
patients with hemophilia A is still intact, a bleeding tendency is usually not expected.
However, since hemophilia is a serious condition, it becomes quickly evident that coagulation
must proceed in a manner different to that of the two pathways, which are seemingly independent
of one another.
Therefore, we’ll be presenting a new coagulation model termed the cell-based model of coagulation.
It takes into account recent findings on coagulation in blood vessel injury and offers a better
way of describing conditions such as hemophilia.
Let’s start with an overview on clotting factors. We’ll be addressing several aspects
that may make coagulation initially appear confusing.
There are 12 factors that are especially important in coagulation. These are indicated by the
Roman numerals 1 to 13. So there are 12 factors but 13 numbers? Factor six later turned out
to be an activated form of factor five. As a result, there is no factor with the number
six in use.
Factor five is not the only factor with two different forms. Most factors have an inactive
and active form. Active forms are indicated by a small ‘a’.
Some factors are also identified by a common name, especially the first four factors. The
term fibrin is used for factor one and thrombin for factor two. Factor three is also known
as tissue factor and factor four as calcium. So, now you can see why understanding coagulation
can be so complex. The topic becomes more complicated considering that some factors
occur as a complex, which are also assigned other names.
But don’t worry, we’ll take you step-by-step through this topic. We’ll start with a closer
look at the order in which the various factors participate in the coagulation cascade, which
will then be followed by a comparison with the new cell-based model.
The extrinsic pathway is initiated by factor three, which forms a complex with factor seven.
This complex can activate factor ten in the common pathway. Factor ten and its cofactor
five can cleave factor two, resulting in the formation of thrombin. In turn, thrombin cleaves
factor one to fibrin, which forms fibrin strands. In addition, the intrinsic pathway can be
initiated by factor twelve, which is, for example, activated on negatively charged surfaces
such as glass. Subsequent activation of factors eleven, nine, and eight lead to the initiation
of the common pathway.
The factors are now arranged in order according to the classical coagulation cascade. The
first aspect that becomes evident is that this order appears quite random. This has
a historical basis. The factors were numbered in accordance to the order in which they were
discovered. It is only at a later stage that it became clear that the various factors interact
in a different order. Putting aside this disarrangement in numbering, the principle of coagulation
is actually quite clever. Most factors are proteases and each factor activates downstream
factors. The result is a gradual activation, a cascade. There are two advantages to this
type of activation.
It enables the precise control of coagulation on different levels and also a sudden increase,
or a chain reaction. To keep it simple: In this and the following images, we won’t
show the difference between inactive and active clotting factors. We hope this introduction
has removed some stumbling blocks on the road to understanding this topic.
So, let's move on to the model of cell-based coagulation in the next Chalk Talk episode.