The Peculiarities Of Blood Clotting Process

The blood is a fluid in human body and it is a part of the cardiovascular system, it consists of 55% of plasma and 45% of blood cells which transports oxygen, nutrients, and hormones to our cells and eliminates metabolic wastes from cells such as Co2 and delivers it to the appropriate organ for elimination and excretion, it also helps the body to fight against infections and diseases. The majority of the blood plasma consists of water, it also contains nutrients, metabolites, salts, hormones and plasma proteins, one of the most important protein in the coagulation process is a plasma protein called fibrinogen that binds to the platelets and form the clot, in addition to fibrinogen, many more clotting proteins are present in the plasma in form inactive precursors and can be activated by cleavage.

Blood cells are divided into 3 types:

1. Erythrocytes: Are biconcave shaped cells that contain hemoglobin and lack nucleus and mitochondria when they mature, as a result they are very efficient at transporting oxygen and nutrients to cells and eliminating the waste materials from them.
2. Leukocytes: Compared to Erythrocytes, Leukocytes are much larger complete cells with a nucleus and mitochondria, their main function is to provides the body’s specific immune response by secreting cytokines and activating other specialized leukocytes when a pathogen enters the body.
3. Thrombocytes: are specialized disc like cells that aid in intravascular clotting by forming a plug at the site of vascular damage or secreting regulators of the clotting process and vascular repair, like erythrocytes, Thrombocytes also lack nucleus, they originate from budding of the cytoplasm of Multinucleated cells residing in the bone marrow known as Megakaryocytes. platelets contain 3 types of granules which are secreted during the clotting process, these granules are:

• A. Electron dense granule
• B. α – granule
• C. Lysosomal granule

Clotting factors are arguably the most essential components of hemostasis. Hemostasis is the body’s physiologic response to vascular endothelial injury, which results in a series of processes that attempt to retain blood within the vascular system through the formation of a clot. Hemostasis can be further divided into primary and secondary hemostasis. Primary hemostasis, which results in the formation of a soft platelet plug, involves vasoconstriction, platelet adhesion, platelet activation, and platelet aggregation. Secondary hemostasis is primarily defined as the formation of fibrinogen into fibrin, which ultimately evolves the soft platelet plug into a hard, insoluble fibrin clot. Within primary and secondary hemostasis, 3 coagulation pathways exist: intrinsic, extrinsic, and common. The intrinsic pathway responds to spontaneous, internal damage of the vascular endothelium whereas the extrinsic pathway becomes activated secondary to external trauma. Both intrinsic and extrinsic pathways meet at a shared point to continue coagulation, the common pathway.

The Start of Coagulation Process

When a blood vessel is damaged, a series of reaction start to take place at the site of the damage that starts with vessel constriction and ends with the formation of the mechanical clot, it consists of these steps:

1. Vascular spasm

The first step is vascular spasm in which the damaged endothelium cells secret a chemical called endothelin that causes the smooth muscles surrounding the muscle to contract, decreasing the diameter of the blood vessels and ensuring minimal blood loss. The smooth muscles can also contract as a result of myogenic mechanism due to the direct contact between the muscle and the damaged vessel.

2. Platelet plug formation

Next, the damaged cells release collagen, protein called von Willebrand factor (vWF), and other materials, these released materials bind to a glycoprotein called GpIb found on the cell membranes of the platelets, activating them changing its shape from disc shaped to spherical, this binding allows the adhesion of the nearby platelets to the damaged site. When a platelet binds to a vWF, it releases some of the contents of its dense granules and α granules such as ADP, Thromboxane A2 and serotonin, ADP and Thromboxane A2 stimulate other platelets to bind to each other through another glycoprotein known as GpIIb-IIIa making the platelet plot larger and denser. Thromboxane A2 also works with serotonin to enhance the vascular spasm effect by contracting the smooth muscles and narrowing the vessel.

3. Coagulation

Activation of clot formation occurs through interlocking pathways, termed the intrinsic and extrinsic pathways. The intrinsic pathway starts when Factor XI is activated by thrombin and changed to XIa, which then activates Factor IX and changes it to IXa, then Factor VIII is changed to VIIIa by thrombin. The combination of Factor IXa and VIIIa activates Factor X to Xa. From this point the pathway is known as the common pathway as it is common between both the intrinsic and extrinsic pathway. Thrombin changes Factor V to Va, Factor Xa and Va together activates the zymogene prothrombin (Factor II) and changes it to thrombin (Factor IIa), this thrombin is used to activate previous Factors in the reaction and to activate the soluble fibrinogen (Factor I) by changing it to the insoluble fibrin (Factor Ia) which is also known as a soft clot. Th final step in the coagulation process is changing the soft clot fibrin to the hard clot cross linked fibrin, this occurs when Factor XIII is changed to XIIIa by thrombin, this Factor XIIIa then Cross links the fibrin molecules, these cross linked fibrin molecules ensures that the platelet aggregation at the damaged site wont break off to cause embolism. Most of these reactions in the cascade also require calcium, phospholipid membranes and platelet factors in order to occur.

The extrinsic pathway is much shorter than the intrinsic pathway, it is activated when the tissue factor is released into the blood by the damaged cells, these tissue factors along with PL and Ca change Factor VII to VIIa, then the activated Factor VIIa changes Factor X to Xa, from this point onwards the common pathway occurs. As we can see the extrinsic pathway can activate Factor X sooner and by a smaller number of reactions than the intrinsic pathway. The hemostatic plug formed at the end of coagulation release chemicals such ad PDGF and VEGF to help regenerate and repair the blood vessels and the surrounding smooth muscle and connective tissue.

Note that thrombin also acts as a positive feedback to the previous steps of the reaction thereby increasing the rate of the reaction as time passes.

Fibrinolysis

After successful formation of the plug, further developing of the plug must be prevented, this is accomplished by switching off blood coagulation and turning on fibrinolysis, the enzymatic breakdown of fibrinolysis is accomplished by a protein called plasmin, which exists in the blood in an inactive form plasminogen, this zymogen naturally has a high affinity to fibrin and it is activated at an efficient rate at the surface of the plug by proteins known as Plasminogen activators. Activated protein C (APC), which is an inhibitor of the blood coagulation cascade, also stimulates the release of Plasminogen activators from the damaged tissues, and simultaneously inactivates an inhibitor of plasminogen activator, PAI-1.

Plasminogen can be activated by either tissue plasminogen activator (tPA) or single-chain urokinase (U-PA). PAI-1 blocks tPA action. Streptokinase binding to plasminogen allows autocatalysis to form plasmin. Circulating α2-antiplasmin blocks the activity of any soluble plasmin that may be in the blood.

Regulators of the blood clotting cascade

Many regulators participate in this cascade reaction, either by initiating or inhibiting the reactions in the process, the main regulators of this cascade include:

1. Thrombin

Thrombin has both feedback amplification and feedback inhibition. The amplification part (also known as prothrombic effect) is when thrombin stimulates its own production by activating Factor XI, VIII, V, thus speeding up its own production rate. Thrombin also promotes clot formation by activating platelet aggregation, stimulating the release of factor VIII from vWF and changing factor XIII to factor XIIIa.

The inhibitory effect of thrombin (also known as antithrombic effect) happens when thrombin binds to the cell receptors called thrombomodulin on the surface of endothelial cells, Thrombomodulin diminishes the clotting functions by forming a complex called thrombin thrombomodulin complex (TTC), this complex activates protein C and S, which has anticoagulant effects.

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2. Protein C and S

Protein C and its cofactor protein S are vitamin K dependent regulators of the coagulation process. They are synthesized by the liver in a process called γ-carboxylation, it inhibits the process by inhibiting Factor V and VIII.

After activation by TTC, protein C and S form a complex together, then this activated protein C (APC) suppresses coagulation by destroying Factor Va and VIIIa. APC also stimulates cells to to increase the secretion of prostaglandin I2 (PGI2), which reduces platelet aggregation.

3. Serpins

Serpins (Serine protease inhibitors) are small protein inhibitors that exist in high concentrations in the blood and tissues. These inhibitors each contain an active site that match the shape of a serine protease, thus acts as a trap for that specific protease. An example of these serpins include antithrombin III. Each molecule of antithrombin III binds and inactivates a molecule of thrombin in an irreversible reaction, its can also inhibit Factor XIIIa, XIa, IXa, and Xa.

4.Thromboresistance of vascular Endothelium

Normal endothelial cells are inhibitors of the coagulation process, they are negatively charged so they naturally repel platelets which are also negatively charged. Endothelial secret many powerful inhibitors such as PGI2 and nitric oxide that inhibit platelet aggregation. Endothelial cells also secret powerful inhibitors to thrombin and heparan sulfate. Heparan Sulfate is a glycosaminoglycan that promote the effect of antithrombin III. These actions by intact endothelium cells makes them a regulator in the coagulation process.

5. Plasmin

As we noted earlier, plasmin inhibits the cascade process by breaking down and degrading the fibrin mesh that surrounds the platelet aggregation.

Effects of drugs on the coagulation process. Numerous drugs effect the coagulation process, these drugs are classified intro 3 types:

1. The heparins

The heparins are activators of antithrombin III, which is an inhibitor to thrombin and some of the coagulation factors. Two type of heparins exist, High molecular weight (HMW) and low molecular weight (LMW). The difference between these two types of heparins are that LMW heparins have more specific interactions with parts of the coagulation process and are much easier to monitor on patients than the HMW heparins, which have more nonspecific interactions in the body such as binding to the plasma proteins and cell surfaces. Heparin is used to treat or prevent clots in conditions where there is a high risk of clot formation and thromboembolism.

2. Vitamin K antagonists.

Drugs such as Warfarin, Dicoumarol and phenindione are Vitamin K antagonists, meaning they oppose Vitamin K regeneration. The most common Vitamin K antagonist drug is warfarin, which interferes with blood clotting by inhibiting the Vitamin K reductase enzymes, thus blocking the production of Vitamin K and γ-Carboxylation, without them, Factor II, VII, IX, X, Protein C and S cannot form complexes and participate in the coagulation process. Warfarin is useful for people at risk of developing harmful clots in the blood, such as in certain clotting disorders.

3. Specific inhibitors of thrombin

These are based on hirudin and are direct inhibitors to thrombin. Hirudin was first discovered on blood sucking organisms, these organisms react to blood clotting process by releasing hirudin because they can’t suck the blood when it is coagulated. But hirudin by itself can be dangerous, because it binds to thrombin in an irreversible reaction and requires constant monitoring of the patient. To overcome this problem, a type of hirudin is used, which has a 20 amino acid sequence known as bivalirudin, its is much safer for long term use because its actions are reversible.

Common disease and disorders related to blood clotting

Many disease and disorders that are related to blood clotting exist, they can cause extensive and continuous bleeding for no reason or promote platelet aggregation when there is no damage to blood vessels. Some of them are Genetical, meaning that they can be inherited from the parents, while others are environmental. The common diseases are:

1. Hemophilia Type A and Type B

Both Type A and B is a disorder that is characterized by the absence of clotting Factors, Type A lacks Factor VIII while Type B lacks Factor IX, causing reduced or the lack of clot formation in bleeding situations. It is genetically inherited by genes that are recessive and are located on the X chromosome so its more common in males than females. Its symptoms can be mild, moderate and severe, including excessive and prolonged bleeding during a cut or surgery, , pain and swelling in joints as a result of bleeding, and in complicated cases it can cause numbness, repeated vomiting and double vision. Hemophilia Type A is more common and can be more severe than Type B.

2. Clotting Factor deficiencies

It is a rare disorder in which one or more clotting factors (II, V, VII, X, XII) is absent or not working properly, they can lead to abnormal blood clotting during bleeding.

3. Van Willebrand’s disease

One of the most common bleeding disorders, it is the result of the absence of the Van Willebrand’s Factor in the blood, which is very important for the coagulation process and platelet aggregation at the damaged site. Without vWF clotting will not occur at the damaged site which results in excessive bleeding.

Many more diseases exist that is related to blood clotting, such as Factor V Leiden, Bernard-Soulier syndrome, Thrombocytopenic purpura and kwashiorkor (malnutrition of protein resulting in low concentration of clotting factors).

Conclusion

From the topics and process I mentioned above, we can conclude and summarize the following points:

• •emostasis is divided into 3 steps, these include vascular spasm, platelet aggregation and coagulation, during which the vessel is dilated to increase blood flow, platelets are activated and aggregated at the site of bleeding and several clotting factors participate in a cascade of reactions to form the fibrin mesh.
• Fibrinolysis is breakdown of the fibrin mesh by the plasma protein plasmin, which is a regulator of the blood clotting process along with APC, Thrombin and serpins
• Several drugs effect the blood clotting cascade, these include the heparins (activators of antithrombin III), Vitamin K antagonists such as warfarin (inhibits vitamin K reductase) and direct thrombin inhibitors based on hirudin.
• Many clinical conditions result in deficiency of clotting factors or receptors or any of the substrates that participates in the blood clotting process, such as Hemophilia A and B, which are X- linked disorders that cause extensive bleeding in joints and during cuts. Another example is clotting factor deficiencies, although pretty rare, they can be critical conditions. And lastly, there is Van Willebrand’s disease, which is characterized by absence of vWF in the blood.

References

1. Marks’ Basic Medical Biochemistry (A Clinical Approach) – Lieberman & Marks – 4th Edition – Section 8 – Chapter 45 – Blood plasma proteins, Coagulations and Fibrinolysis.
2. Article about Biochemistry of clotting factors. https://www.ncbi.nlm.nih.gov/books/NBK507850/
3. Anticlotting mechanisms, Physiology and Pathology. https://academic.oup.com/bjaed/article/13/3/87/278964
4. Warfarin. https://www.uptodate.com/contents/warfarin-coumadin-beyond-the-basics
5. Bleeding disorders. https://www.healthline.com/health/bleeding-disorders#types
6. Vitamin K antagonist drugs. https://www.drugbank.ca/categories/DBCAT002267
7. Heparins. https://www.drugs.com/drug-class/heparins.html
8. Symptoms and causes of Hemophilia. https://www.mayoclinic.org/diseases-conditions/hemophilia/symptoms-causes/syc-20373327
9. List of anticoagulant drugs. https://www.medicinenet.com/anticoagulants_drug_class_of_blood_thinners/article.htm#who_shouldnt_take_anticoagulants