Introduction
Hemostasis is the mechanism that regulates the cessation of bleeding upon encountering an injury or trauma. It mostly entails responding to the wound by stopping blood loss and starting damage repair. Hemostasis is essentially a group of multiple processes rather than a single process. When a blood clot forms in the body, all of these processes co-occur despite their appearance as separate ones. Several factors are found in the body, and they work in unison to carry out this intricate operation. Thrombin is one of these factors and is important in accomplishing successful blood coagulation. However, its unique characteristics make it stand out. This article discusses the role of thrombin and its application in medicine.
What Is Thrombin?
Thrombin is an enzyme that is normally not found in the blood. It is only generated when there is vascular damage or in response to an injury. Thrombin births from prothrombin and carries out the most important function of converting fibrinogen into fibrin. Following vascular injury, a series of enzymatic reactions lead to thrombin generation. It plays a pivotal role in the blood coagulation process and is one of the key components of the coagulation cascade. This coagulation cascade is divided into intrinsic and extrinsic pathways. These pathways converge at converting Factor X to its active form, Xa. This Xa, Va, and calcium form the prothrombinase complex on the activated platelet surface. Prothrombinase generates prothrombin to thrombin, which is at the forefront of several additional clotting processes.
What Is the Mechanism of Action of Thrombin?
The blood clotting pathway that is innately present in the body is quite complex. Several factors - clotting factors - contribute to one same goal - stoppage of bleeding - by participating in the coagulation process and playing their part well. Thrombin is one of these factors and has several roles to play in this process:
-
It acts as a dual molecule by playing the roles of procoagulant and anticoagulant. As a procoagulant, it converts soluble fibrinogen to insoluble fibrin, which intertwines to form the fibrin clot of the hemostatic plug.
-
Thrombin acts as a catalyst in several reactions of the blood-coagulation pathway. It has a huge role in activating factors V, VIII, and XI. The activation of factor XI, especially, ensures the protection of the fibrin clot by preventing fibrinolysis.
-
It is an automated enzyme that activates the factors V, VIII, and IX.
-
Thrombin also activates factor XIII to XIIIa, which strengthens the fibrin clot by promoting cross-linking of fibrin fibers.
-
Thrombin stimulates the platelet cell membrane receptors, further encouraging platelet aggregation.
-
As an anticoagulant, thrombin promotes fibrinolysis by binding to a membrane protein called thrombomodulin. Upon interacting with thrombin, thrombomodulin converts it into an anticoagulant enzyme by activating protein C. Protein C is an inhibitor of the blood-clotting pathway.
-
Due to its chemotactic qualities, thrombin also significantly impacts inflammation or damaged vessels.
Both thrombin's procoagulant and anticoagulant roles are crucial to maintaining a harmonious balance in hemostasis regulation. The procoagulant ensures the conversion of fibrinogen to fibrin and promotes cross-linkage of the fibrin fibers. On the other hand, the anticoagulant thrombin ensures protein-C activation, which inactivates the factors Va and VIIIa, ultimately preventing the risk of venous thrombosis.
How Is Thrombin Utilized as a Biotherapeutic Agent?
Thrombin has been a subject of top research owing to its unique properties and beneficiary outcomes. It is indicated that thrombin can prove to be an excellent biotherapeutic agent. Several types of thrombin are derived to achieve this, assisting medical professionals in unimaginable ways today. The three derivatives of thrombin currently in use include:
-
Bovine thrombin.
-
Human thrombin.
-
Recombinant thrombin.
Bovine thrombin was one of the first derivatives to be discovered for its application as a hemostatic agent to control undesirable bleeding during several surgical procedures. However, many patients showcased adverse reactions to its use, thereby resulting in the discovery of human and recombinant thrombin. Apart from hemostasis, they are also utilized for the functions of fibrin sealants to seal tissues and wound closure, as well as tissue engineering techniques. It can behave as a scaffold in regenerative medicine.
Thrombin also treats surgical complications like arteriovenous fistula, vascular access bleeding, etc. Targeted local application or injection of thrombin agent is done directly to the site to seal abnormal vascular connections. Thrombin products are extensively used with other absorbable hemostatic agents such as gelatin sponge, microfibrillar collagen, and oxidized regenerated cellulose. In addition, thrombin products help heal several pseudoaneurysms by quickly creating a fibrin polymer when thrombin is injected percutaneously into the pseudoaneurysm. However, the Food and Drug Administration (FDA) has yet to approve this operation.
What Are the Adverse Effects of Thrombin Use?
The FDA has authorized the use of all three thrombin products—human, bovine, and recombinant—for topical application alone. However, several adverse effects are linked to their usage.
-
Bovine thrombin, derived from bovine blood, has shown adverse effects, such as forming antibodies against it. This indicates that the body cannot accept the derivative and rejects it. As a result, hemorrhagic complications, thromboembolic events, anaphylaxis, and even death have been reported as adverse reactions to bovine thrombin.
-
Human thrombin, obtained from human blood or plasma, carries the inherent risk of transmitting bloodborne infections, provided the donor material is contaminated. Despite strict screening protocols for blood products, there is still a risk for transmission-related infections. In some unfortunate cases, blood transfusion may be necessary to control the complications from the use of human thrombin.
-
Recombinant thrombin is known to be derived from hamster blood. People allergic to hamster proteins can show serious hypersensitive reactions, ultimately rejecting the thrombin. However, no such cases have been reported regarding recombinant thrombin to date. Recombinant thrombin is found to be relatively more acceptable compared to bovine thrombin.
Conclusion
The use of thrombin derivatives requires strict monitoring and surveillance of any adverse reactions, hypersensitivity, coagulopathies, or bleeding disorders encountered upon its use. Thrombin has proven its efficacy as a drug in medicine and is a key component in achieving hemostasis. No overdose incidents involving thrombin products have been documented.
