F3 - coagulation factor III, tissue factor | Elisa - Clia - Antibody - Protein

Background

Coagulation Factor III, also known as Tissue Factor (TF) or Thromboplastin, is an essential component of the hemostatic process, serving as the primary initiator of blood coagulation. Tissue Factor is a transmembrane glycoprotein that is expressed in subendothelial tissues and certain cell types and plays a pivotal role in initiating the extrinsic coagulation pathway. When there is vascular injury, Factor III is exposed to the circulating blood, enabling it to bind with Factor VII (FVII) to form a TF-FVIIa complex that subsequently activates downstream factors, including Factor X (FX) and Factor IX (FIX), leading to thrombin generation and ultimately the formation of a fibrin clot. Beyond hemostasis, tissue factor is involved in inflammatory pathways, angiogenesis, cell signaling, and tissue remodeling, underscoring its multifunctionality in various physiological and pathological processes.

Protein Structure

Tissue Factor is a 47 kDa transmembrane glycoprotein comprising 263 amino acids organized into three major domains:

Extracellular Domain (Residues 1-219):

• This domain is responsible for the primary function of TF—binding and activating Factor VII. Structurally, it consists of two fibronectin type III-like domains. Each of these domains contains β-sheets arranged in a sandwich formation, contributing to TF’s structural stability and its capability to interact with Factor VIIa.
• Key binding sites within this domain enable interaction with Factor VII, forming the TF-FVIIa complex. This complex catalyzes the activation of downstream coagulation factors, triggering the extrinsic coagulation cascade. Additionally, this domain includes specific regions for potential glycosylation, enhancing TF stability and modulating its availability on the cell surface.

Transmembrane Domain (Residues 220-242):

• The transmembrane domain consists of a hydrophobic sequence that anchors TF into the plasma membrane. This positioning ensures that the extracellular domain remains exposed to circulating blood, ready for Factor VII binding and coagulation initiation upon tissue damage. The transmembrane region contributes to the protein's orientation and stability on the cell surface.

Cytoplasmic Domain (Residues 243-263):

• The short cytoplasmic tail is involved in cell signaling and interactions with intracellular proteins, contributing to cellular responses to environmental changes. This domain contains phosphorylation sites that modulate TF’s interactions with cytoplasmic proteins and signaling pathways, including those involved in cellular responses to inflammation and injury.
• The phosphorylation of serine residues within this domain regulates TF trafficking, cellular localization, and shedding from the membrane, allowing it to modulate its activity and availability according to cellular needs.

Classification and Subtypes

Tissue Factor is classified as a transmembrane glycoprotein and a member of the class II cytokine receptor family, due to its role as a receptor for Factor VII. It has no subtypes, as it is encoded by the F3 gene and is ubiquitously expressed in various tissues, particularly those exposed to blood, such as vascular smooth muscle cells and certain epithelial tissues. TF expression is tightly regulated, typically remaining low in the endothelium but upregulated in response to injury, inflammation, or other stimulatory signals, ensuring its activity is appropriately modulated in hemostasis and wound healing.

Function and Biological Significance

Hemostasis and Coagulation Initiation:

• Tissue Factor’s primary role is to initiate the extrinsic pathway of coagulation. Upon vascular injury, the exposure of TF to blood enables it to bind to FVII, forming the TF-FVIIa complex. This complex activates Factor X, leading to thrombin formation, which in turn cleaves fibrinogen into fibrin, forming a stable blood clot. This mechanism provides a rapid response to vascular damage, preventing blood loss and supporting wound healing.
• TF expression is especially critical in tissues with a high risk of injury and blood exposure, allowing for rapid coagulation at injury sites. Endothelial cells, however, are generally TF-deficient, providing an anticoagulant environment under normal conditions.

Role in Inflammation and Immune Response:

• Tissue Factor is also involved in immune modulation and inflammation. By interacting with protease-activated receptors (PARs), particularly PAR-2, the TF-FVIIa complex can trigger signaling cascades that result in cytokine release and upregulation of adhesion molecules. This promotes leukocyte recruitment to injury sites and supports tissue repair, linking TF’s role in coagulation to immune response and inflammation.
• Furthermore, during inflammatory conditions such as sepsis, TF expression is upregulated in monocytes and macrophages, amplifying its role in immune response modulation.

Angiogenesis and Tumor Growth:

• TF has a recognized role in angiogenesis and tumor progression. The TF-FVIIa complex can activate cellular pathways, including those involving MAPK and PI3K/Akt, which promote endothelial cell migration, proliferation, and new blood vessel formation.
• Cancer cells often upregulate TF, which facilitates angiogenesis and metastatic potential by promoting vascularization around tumors and facilitating cancer cell entry into circulation. TF has therefore become a therapeutic target in cancer research, where strategies aim to inhibit its proangiogenic effects.

Role in Thrombosis and Atherosclerosis:

• Dysregulated or excessive TF expression contributes to thrombotic events, including deep vein thrombosis, pulmonary embolism, and myocardial infarction. TF is commonly found in atherosclerotic plaques, where its exposure due to plaque rupture triggers local thrombosis, leading to cardiovascular events.
• In atherosclerosis, TF upregulation occurs in macrophages, smooth muscle cells, and foam cells, which underlies the pro-thrombotic environment characteristic of this disease.

Clinical Issues

Due to its pivotal roles in coagulation, inflammation, and cancer, abnormalities in TF expression or function are associated with various clinical conditions:

Thrombosis and Cardiovascular Disease:

• Elevated TF levels or uncontrolled TF expression leads to thrombosis, particularly in pathological conditions such as atherosclerosis, where plaque rupture exposes TF to circulating blood, triggering clot formation. Anti-TF therapies are being researched to mitigate these risks by targeting TF-FVIIa interactions or inhibiting TF expression in vulnerable plaques.

Sepsis and Disseminated Intravascular Coagulation (DIC):

• In severe inflammatory states like sepsis, monocytes and endothelial cells upregulate TF expression, leading to disseminated intravascular coagulation, where widespread coagulation occurs, causing microthrombi formation, organ failure, and severe bleeding. Monitoring and modulating TF activity in septic patients can help mitigate the risk of DIC and associated complications.

Cancer:

• TF overexpression in certain cancers correlates with tumor aggressiveness, angiogenesis, and metastatic potential. High TF expression in tumors, particularly those of the breast, pancreas, and prostate, contributes to cancer cell invasion and metastasis. Efforts are ongoing to develop anti-TF therapies to prevent tumor progression and metastasis by targeting TF expression in cancer cells and the surrounding stroma.

Hemophilia and Other Coagulation Disorders:

• In hemophilia, therapeutic approaches include using TF-based treatments to enhance coagulation. Recombinant TF is explored as a treatment option for hemophilia patients, where it can be used to restore hemostasis in situations where traditional replacement therapies are ineffective.

Summary

Tissue Factor (F3) is a crucial transmembrane glycoprotein involved in hemostasis, functioning as the primary initiator of the extrinsic coagulation cascade. Its structured domains allow it to interact effectively with Factor VII, facilitating thrombin generation and fibrin clot formation. Beyond coagulation, TF influences inflammation, immune response, and angiogenesis, linking it to a broad spectrum of biological functions. Dysregulation of TF expression or activity is implicated in several clinical conditions, including thrombosis, cardiovascular diseases, cancer progression, and inflammatory disorders. Consequently, Tissue Factor serves as a critical therapeutic target in developing anti-coagulant, anti-inflammatory, and anti-cancer treatments.