Pathophysiology of Thrombus Formation

Thrombosis is a pathologic event that results in the obstruction of coronary, cerebral, or peripheral blood flow.2 A thrombus is formed by the two major components of the coagulation system: platelets and coagulation factors. Normally, the endothelial cell lining of the vessels maintain an antithrombotic status by several mechanisms that prevent platelet adhesion to the vessel wall, including: maintaining a transmural negative electrical charge; releasing prostacyclin (PGI2), which prevents platelet aggregation; and activating the fibrinolytic pathway and protein C, which degrades the coagulation factors.3

In case of vascular injury, platelets and plasma clotting factors become exposed to the subendothelial collagen and the endothelial basement membrane, which releases adenosine diphosphate (ADP), a potent platelet aggregator, and tissue factor, which launches the clotting cascade (Figures 1 and 2). Platelets adhere to the vessel wall and undergo conformational changes, which enhances more platelet aggregation. Moreover, glycoprotein (GP) IIb/IIIa receptors are upregulated and subsequently fibrinogen and von Willebrand's factor bind to activated platelets via GP IIb/IIIa receptors forming the platelet plug.4

Activated platelets acquire an enhanced capacity to catalyze the interaction between activated coagulation factors. These factors are generally circulating in the blood in an inactive form (zymogens). The clotting cascade consists of two separate initial pathways (intrinsic and extrinsic) that converge into a final common pathway, which ends by activation of factor X to Xa and conversion of fibrinogen to fibrin (Figure 2). The extrinsic pathway is important for the initiation of fibrin formation while the intrinsic pathway is involved in fibrin growth and maintenance.4

The extrinsic pathway is triggered by tissue factor, also called thromboplastin (a lipid-rich protein material released after vascular injury). Thromboplastin combines with activated factor VIIa to convert factor IX to activated factor IXa in the intrinsic pathway and factor X to activated factor Xa in the extrinsic pathway. Factor VII is activated by IXa or XIIa of the contact system. This process takes 15 s.

The intrinsic pathway is initiated by activation of factor XII by the high-molecular-weight kininogen (the precursor of vasoactive peptide, bradykinin) and kallikrein in the presence of collagen. Factor XIIa converts factor XI to XIa, which in turn activates factor IX to factor IXa, and subsequently factor X to Xa. Activated factor Xa then binds with factor Va, Ca2 +, and phospholipids (PLs) from the platelet membrane to form Xa-Va-PL complex (prothrombinase), which converts prothrombin to thrombin. Thrombin finally cleaves fibrinogen to release isolated fibrin monomers, which polymerize with each other to form complex fibrin. Factor XIII, which is also activated by thrombin, stabilizes fibrin complexes and hence thrombus formation.

There is tight control over the coagulation system; once factor Xa is formed, it binds to tissue factor pathway inhibitor (TFPI), which inhibits further activation of factor Xa and factor Va. Other control mechanisms include

Figure 1 Triggering of coagulation cascade

Xa+Va+Ca+PL (prothrombinase)

Prothrombin -


Fibrinogen i

Fibrin monomers

I XIIa Fibrin polymer

Figure 2 Diagram showing the coagulation cascade. PL, phospholipids.

thrombin activation of the fibrinolytic pathway and the presence of antithrombin III, which prevents clotting factor activation, protein C, which inactivates factor Va, and protein S, which acts as a cofactor for protein C where they form a complex to inactivate factor VIIIa.3

Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook

Post a comment