Now that the platelet plug is complete, its time for secondary hemostasis to stabilize it. In order to strengthen the weak platelet plug, several coagulation factors and cofactors are required. The stabilization of the platelet plug results in a “coagulation cascade” that ultimately changes the fibrinogen linking the platelets with a crosslinked and more stable fibrin. The coagulation factors of the coagulation cascade are mostly produced by the liver and circulate inside the blood vessels in an inactive state. To activate these factors they must be exposed to trauma, an activating substance, or extravascular material.
In order for secondary hemostasis to take action, a prothrombin activator must be generated. The combined actions of the intrinsic pathway, extrinsic pathway and the prothrombin activator complexes lead to an explosive burst of the enzyme thrombin (Factor IIa) which generates more prothrombin activation and also activates coagulation factor VIII. Although the roles of the intrinsic and extrinsic pathway complexes may appear to be somewhat redundant, they are important integrating several subjects in medicine. The coagulation cascade contains physiology, biochemistry, pharmacology, microbiology, pathology and genetics.
The First Step in the Coagulation Cascade: Activation of Factor VIIIa and Factor V
During the initial stages of the hemostatic event, low levels of both activated factor X (factor Xa) and activated factor IX (facter IXa) are generated. Once generated, the limited amounts of factor Xa bind to available membrane sites and convert picomolar amounts of prothrombin to thrombin. This thrombin then activates factor VIII (required by the Intrinsic Pathway) and factor V, allowing the initial formation of the intrinsic prothrombin activator complexes. Thus, the time period in which factor Xa directly generates picomolar amounts of thrombin is referred to as the initiation phase of blood coagulation. An alternative initiation of factor X to factor Xa has been identified on stimulated cells of monocytic and myeloid differentiation involving the specific adhesive receptor Mac-1. A platelet factor Xa receptor has been described as important in mediating prothrombin binding via factor Xa binding to platelet factor Va.
|Factor III||Tissue Thromboplastin
Or Tissue Factor
|Platelets and endothelium|
|Factor IV||Calcium (Ca++)||Bone and GI|
|Factor V||Proaccelerin, Labile Factor, & Ac-Globulin (Ac-G)||Liver and Platelets|
|Factor VII||Serum Prothrombin Conversion Accelerator (SPCA), Proconvertin, or Stable Factor||Liver|
|Factor VIII||Antihemophilic Factor A (AHF), or Antihemophilic Globulin (AHG)||Endothelium|
|Factor IX||Plasma Thromboplastin Component (PTC)||Liver|
|Factor X||Stuart Factor||Liver|
|Factor XI||Plasma Thromboplastin Antecedent||Liver|
|Factor XII||Hageman Factor||Liver|
|Factor XIII||Fibrin Stabilizing Factor||Platelets|
|High Molecular Weight Kininogen (HMWK)||Fitzgerald Factor||Liver|
Intrinsic Pathway: Activation of Factor XII and Platelets
The intrinsic pathway can be activated by contact of blood with exposed subendothelial collagen or trauma to the blood (particularly the platelets). This is why this pathway is also known as the “contact” pathway. Contact with subendothelial collagen or with phospholipids released by platelets activates factor XII. This causes the release of platelet phospholipids containg Platelet Factor 3 (also released in platelet trauma).
The activated Factor XII (XIIa) enzimatically acts on factor XI but High Molecular Weight Kininogen (HMWK) and is accelerated by prekallikrein. Factor XI acts enzymatically on factor IX but requires Calcium (Ca++) also known as factor IV. Now we reach a regulatory step in the coagulation cascade. In order to activate Factor X, an activated Factor VIII is required. Factor VIII is activated by Thrombin (factor IIa) in the initial stages of coagulation, as explained earlier. The activated factor VIII is joined with factor IXa, Platelet Phospholipids and Platelet factor 3 to activate Factor X. Activated Factor X continues in the Common Pathway.
The extrinsic pathway begins with traumatized vascular wall or traumatized extravascular tissues that come in contact with blood. Traumatized tissue releases several factor complexes called Tissue Factor or Tissue Thromboplastin. These factor complexes are composed of phospholipids from the membranes of the damaged or injured tissue with an added lipoprotein complex that functions mainly as a proteolytic enzyme that can activate factors VII and X. When tissue factor released from traumatized tissue activates factor VII, the Extrinsic Pathway begins. The lipoprotein complex of tissue factor then joins with the activated factor VII (VIIa) and with Ca++. The complex can enzymatically activate Factor X which will continue in the Common Pathway.
The Common Pathway
In order for the common pathway to continue, a Prothrombin Activator Complex must be formed. Activated factor X (Xa), from either the Intrinsic or Extrinsic pathway, combines with phospholipids released in tissue factors or with phospholipids released from platelets as well as with Factor V to form this Prothrombin Activator Complex. With the presence of calcium ions, this splits prothrombin (factor II) to form thrombin (factor IIa). At first, the factor V is in inactive state and is used as a slow cofactor but once clotting begins and thrombin begins to form, the proteolytic action of thrombin activates factor V (along with factor VIII and factor XIII). Activated factor V then becomes an additional accelerator of prothrombin activation.
Thrombin (factor IIa) causes polymerization of fibrinogen molecules into fibrin fibers. The rate limiting factor in causing blood coagulation is usually the formation of prothrombin activator. The subsequent reactions beyond that point normally occur rapidly to form the clot. Platelets also play an important role in the conversion of prothrombin to thrombin. Much of the prothrombin first attaches to prothrombin receptors on the platelets already bound to the damaged tissue. Thrombin is a protein enzyme with weak proteolytic capabilites. It acts on fibrinogen to remove four low molecular weight peptides from each molecule of fibrinogen, forming one molecule of fibrin monomer that has the automatic capability to polymerize with other fibrin monomer molecules to form fibrin fibers. Many fibrin monomer molecules polymerize within seconds into long fibrin fibers that are stabilized by factor XIII changing the initial weak Platelet Plug into a solid Blood Clot. The blood clot is composed of a meshwork of fibrin fibers, running in all directions and entrapping blood cells, platelets and plasma. The fibrin fibers also adhere to damaged surfaces of blood vessels, therefore, the blood clot becomes adherent to any vascular opening and thereby prevents further blood loss.