After being bombarded with "Cells at Work!", you should know what coagulation waterfall is, right?

Author: Lin Lisha (Kunming Institute of Botany, Chinese Academy of Sciences)

The article comes from the Science Academy official account (ID: kexuedayuan)

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The popular science animation "Cells at Work!" has won the hearts of many netizens. In the second episode "Scratches", the cute platelets have won countless fans. In order to heal wounds and stop bleeding in time, platelets use coagulation factors to help white blood cells defeat bacteria, thereby protecting the world in which cells live.

Image source: bilibili

When a wound bleeds, or when a small bleeding spot is inserted into the needle during blood drawing, we usually stop it with a little pressure, which is mainly contributed by platelets and coagulation factors. After the blood vessel is injured, platelets rush to the wound, and the subsequent activation of the coagulation waterfall supports the platelets in time. Speaking of the coagulation waterfall, you may not be familiar with it. Today, the courtyard er will take you to know the "coagulation waterfall".

What is the coagulation cascade?

In the eyes of scientists, the coagulation process is not just a hemostatic cotton ball or a blood clot, but it looks like Figure 1 (the subscript a indicates the activated state). Like other signal pathways in the body, the coagulation process has a delicate regulation and is vividly called the "coagulation waterfall"; its biochemical essence is a series of enzyme reactions of coagulation factors in plasma. The upstream factors activate their downstream factors, and finally prothrombin (FII) is converted into thrombin (FIIa), which converts soluble fibrinogen (FI) into insoluble fibrin (FIa).

Figure 1. “Coagulation Cascade”, cascade reaction of coagulation factors (subscript a indicates activation state)

Under normal circumstances, the coagulation factors in the body are in an inactive state, just lazily flowing in the blood or isolated by the vascular endothelium. In addition, there are many "gates" in the body to prevent the coagulation waterfall from rushing down and forming blood clots to block normal blood vessels. When we are injured, the coagulation waterfall needs to overcome various resistance forces on the cascade reaction path to form blood clots to block the rupture of the blood vessels and avoid excessive bleeding, which is physiological hemostasis.

Are you a little dizzy when you first see the coagulation cascade (Figure 1)? This is not even including the "gates"; you see, their Roman numerals are not in the order of the cascade reaction, such as FXI-FIX-FX-FII, and some numbers are missing, such as FIII, FIV and FVI. Let's take a look at the "secret history" of the members of the coagulation family.

The logic behind the chaos

In fact, the Roman numerals are numbered in the order in which they were discovered. Dramatically, the upstream coagulation factor XII (FXII) was the last to be added to the coagulation waterfall, and its discovery spanned more than a century from the naming of the first coagulation factor (FI, fibrinogen).

The discovery of FXII stems from an abnormal coagulation function test. In 1958, Dr. Ratnoff found that when Hageman's blood was tested in vitro, the coagulation time was abnormally prolonged. He added all the known coagulation factors to the patient's blood, but still could not correct the coagulation time. This means that the coagulation factor that Hageman lacked has not been discovered yet. Ratnoff became the discoverer of this unknown factor. He named it the Hageman factor after the patient. Because the phenomenon of promoting blood coagulation on the glass surface is related to this factor, it is also called the surface factor. Later, the international nomenclature gave it a standardized name, FXII.

As you can imagine, most other coagulation factors have undergone similar discovery processes and naming changes (see table).

Figure 2. Coagulation factors and their numerical codes

In addition, why are FIII, FIV and FVI not shown in the diagram? The reason is that they are too special. FIII mainly exists in the subendothelial tissue and is the only coagulation factor that is not in the blood. Scientists like to call it tissue factor (TF). The chemical nature of FIV is special. It is the only coagulation factor that is not a protein. The Ca2+ in the diagram is FIV itself. FVI is even more special. People discovered that the coagulation factor thought to be FVI is actually the activated form of FV (FVa). Once the misunderstanding is resolved, it will have nothing to do with it.

History of waterfall evolution

The original coagulation system had only four members including calcium ions. In 1905, Paul Morawitz proposed a prototype of the coagulation process (Figure 3).

On the shoulders of our predecessors, from the 1940s to the 1960s, in just less than 20 years, factors 5 to 12 were discovered one after another by diligent scientists.

During World War II, there are also some epic stories of scientists taking risks. At that time, supplies were scarce, meat was a rare commodity, and there was a test (prothrombin time) that usually used rabbit brain powder rich in tissue factor to induce coagulation. It is said that Owren, the Finnish scientist who discovered FV, risked his life to find two rabbits to complete the experiment during the war.

As more and more coagulation factors were discovered, in order to avoid confusion, scientists established the International Committee on Nomenclature of Coagulation Factors (later the International Society on Thrombosis and Coagulation) in 1954 and decided to use Roman numerals for naming.

Figure 3. Coagulation system models from top to bottom in 1905, 1964, and the 21st century

It is the spirit of bold conjecture and careful verification of these scientists that has given us the coagulation waterfall diagram we have today. Based on this "map", scientists have found targets and developed many drugs for the prevention and treatment of thrombotic diseases, such as rivaroxaban that inhibits FXa, and dabigatran and bivalirudin that inhibit FIIa.

Figure 4. Common anticoagulants rivaroxaban and dabigatran (Image source: Baidu Image)

If the waterfall is not complete...

Among blood diseases, hemophilia (hemo (blood) + (philia) friendship, meaning "bleeding disease") is a well-known blood coagulation disorder caused by the lack of coagulation factors. Patients have a lifelong tendency to bleed after trauma, and severe patients may also have spontaneous bleeding without trauma. Usually hemophilia refers to hemophilia A, which is a deficiency of coagulation factor VIII, while hemophilia B and C are deficiencies of coagulation factors IX and XI, respectively, which are less common.

Hemophilia A and B are X-linked recessive genetic diseases, usually females are carriers and males are the diseased. It is said that in the 19th century, the descendants of Queen Victoria spread hemophilia to the European royal family, which indirectly brought down the Russian royal family (this is the "royal disease" in history).

Figure 5. Hemophilia X chromosome linkage map (picture from the Internet)

Although the earliest record of hemophilia can be traced back to Hebrew before the Common Era (the Jews at that time may have had the concept of heredity, and the patriarch recorded that if a Jewish boy died of bleeding after circumcision, his younger brother could be exempted from circumcision), the understanding of the cause of hemophilia did not gradually become clear until the 20th century. Scientists finally broke through the fog and found corresponding treatments.

Hemophilia is currently still mainly treated with replacement therapy, such as supplementation with fresh frozen plasma, FVIII concentrate extracted from blood, and recombinant FVIII preparations; in addition, scientists are also actively exploring the use of gene therapy to treat hemophilia in order to completely cure patients.

Although the Coagulation Falls may seem a bit dizzying at first glance, you can find the direction if you look at the map carefully. If you don't have a map at all, you won't have any idea where to start. What do you think, dear readers?

Appendix Coagulation Factors and Their Functions

References

1. Wang Zhenyi et al., Basic Theory and Clinical Practice of Thrombosis and Hemostasis, Shanghai Science and Technology Press, 2004;

2. Douglas S, Historical Review COAGULATION HISTORY, OXFORD 1951-1953, Br J Haematol., 1999, 107: 22-32

3. Ratnoff OD, Rosenblum JM. Role of Hageman factor in the initiation of clotting by glass (evidence that glass frees Hageman factor from inhibition). Am J Med. 1958, 25:160–168

4. Margolis J. Glass surface and blood coagulation. Nature. 1956, 178:805–806.

5. Wang Guyun, Yao Hongxia: Advances in the treatment of hemophilia, Medical Review, 2016, 22: 4429-4432

6. Yu Fenggao: The “Royal Disease” of the European Royal Family: Where Does the Hemophilia Gene Come From? | Tianxia, ​​Sohu.com, link: http://www.sohu.com/a/119675375_162197

7. Boehringer Ingelheim: An article that helps you understand the past and present of coagulation medicine, Sohu.com, link: http://www.sohu.com/a/119640212_352501