Fibrin Degradation Products T... Health Article

Definition

When injury occurs to a blood vessel wall, thrombin (a coagulation enzyme) is formed in the first stage of a complicated series of steps called the coagulation cascade. In the second phase, fibrinogen, a coagulation protein made by the liver, is converted to fibrin, which results in the formation of a gel-like meshwork at the site. This fibrin mesh is altered by the action of factor XIIIa which cross-links fibrin polypeptides, forming a stable clot. As the site heals, the clot is broken down by the enzyme plasmin. This process, called fibrinolysis, is initiated by a protein called tissue plasminogen activator that is released from blood vessel cells adjacent to the injured site. Plasminogen activator converts plasminogen to an enzyme called plasmin. The plasmin splits polypeptides from the fibrin clot. These fragments are known as fibrin degradation products (FDP).

Fibrin degradation products are fragments (polypeptides) produced when either fibrin or fibrinogen is broken down by the enzyme plasmin. There are four principal fibrin degradation products called X, Y, D, and E that are liberated in various combinations. When a fibrin clot is broken down by plasmin, the last fragment to be degraded is one consisting of two D and one E subunits. This is split, releasing the E fragment and two D fragments that are covalently linked together. This fragment is called D-dimer, and it is produced from fibrin but not from fibrinogen degradation.

Purpose

A test for FDP may be requested by a physician when excessive bleeding occurs and thrombosis or other serious disorder in the coagulation mechanism is suspected. The FDP assay measures amounts of the fibrin and fibrinogen split products in the blood and directly indicates the level of activity of the fibrinolytic system. High levels of FDP will indicate increased fibrinolysis. Excessive fibrin degradation products are released into the plasma in three main conditions: disseminated intravascular coagulation (DIC), thromboembolytic therapy, and primary fibrinogenolysis. Fragments X, Y, E, and D are released whenever either fibrin or fibrinogen is broken down by plasmin. This degradation occurs in all three situations.

Normal blood plasma does not have significant amounts of D-dimer. It is present in the blood in detectable amounts in several conditions, most notably in disseminated intravascular coagulation (DIC), a rare disruption in normal coagulation in which rapid intramicrovascular (within the blood vessels) coagulation occurs at the same time as fibrinolysis (clot dissolution mechanism). The D-dimer test is used to diagnose DIC. It is also frequently used to help diagnose deep-vein thrombosis (clots in veins); pulmonary embolism (clots in the lungs); the thrombosis of malignancy; and sickle cell anemia (a form of anemia characterized by bleeding episodes); and to monitor the effects of thrombolytic drugs. Thrombolytic drugs that may increase D-dimer levels are barbiturates, heparin, streptokinase, and urokinase. Levels of D-dimer will be elevated in these conditions.

Description

When functioning normally, coagulation and fibrinolysis maintain hemostasis (the normal fluid state of blood in the circulatory system) by regulating clot formation and dissolution. When bleeding occurs, coagulation results in production of a clot at the site of injury, and subsequent fibrinolysis dissolves the clot as the vessel wall heals. The fibrinolytic system is highly complex. A deficiency of plasminogen will result in increased risk of thrombosis. Plasmin is inactivated by several proteases, which are enzymes that catalyze the breakdown of polypeptides. A deficiency of one of these can result in spontaneous bleeding. FDPs themselves can neutralize the activity of some coagulation factors and interferere with normal clot formation. In three conditions, disseminated intravascular coagulation, thromboembolytic therapy, and primary fibrinogenolysis the fibrinolytic activity of the plasma is increased. When this occurs, depletion of coagulation factors, including fibrinogen, results in uncontrolled bleeding. Measurement of FDP and D-dimer are used to identify these causes of hemorrhage.

DIC results in the formation of circulating small fibrin clots formed by a condition that triggers the coagulation cascade. Coagulation factors become depleted and hemorrhage results. DIC is a rapidly progressing condition caused by an underlying disease or trauma, such as the clinical conditions shown below.

• complications of pregnancy, such as toxemia, abortion, cesarean section, placenta previa, and other conditions
• tissue trauma, such as major surgery, severe trauma and burns, rejection of transplant, and heatstroke
• hemolytic processes (destruction of red blood cells), such as transfusion of mismatched blood, drowning, complications of infection, and certain types of poisoning
• malignancies, such as solid tumors, leukemia, and other forms of cancer
• infections, such as bacterial infections, septicemia, Rocky Mountain spotted fever, some viral infections, and parasitic infections
• miscellaneous clinical conditions, such as diseases of the liver and pancreas, uremia, shock, stroke, severe heart failure, and aortic aneurysm (rupture of the aorta)

Coronary artery disease can result in the formation of a blood clot at the site of blockage in the heart vessels. One alternative form of treatment is the administration of a thrombolytic agent such as streptokinase or tissue plasminogen activator. These drugs act by stimulating fibrinolysis, and consequently they may cause both the fibrin clot and fibrinogen to break down. Fibrinogen depletion and accumulation of FDP can interfere with coagulation, causing spontaneous hemorrhage.

Primary fibrinogenolysis is a condition in which fibrinogen is broken down to fibrin in the absence of a clot. Unlike DIC, the formation of intravascular thrombi does not occur. However, if severe, hemorrhage can result because the body's supply of fibrinogen becomes depleted. Causes include shock, hypoxia, heat stroke, hemorrhage, surgery, and liver disease.

FDP tests will yield abnormal results in all three conditions described above because the fragments detected are produced when either fibrin or fibrinogen is split by plasmin. Therefore, the FDP test is not specific for thrombotic diseases such as DIC or deep vein thrombosis. The FDP test uses latex particles coated with anti-D and anti-E. When mixed with plasma, these antibodies react with D and E fragments of both fibrin and fibrinogen, forming a clump.

The D-dimer test measures only the D fragments of fibrin that are covalently bound together. When a fibrin clot is stabilized by factor XIIIa, the D domains of adjacent molecules become linked together. The action of plasmin causes these to be released from the clot as a dimer, which is a molecule composed of two identical simpler molecules. Therefore, the D-dimer test will be positive only when fibrin degradation has occurred. This happens in DIC, after thromboembolytic therapy, and in such thrombotic conditions as deep vein thrombosis and pulmonary embolism, but does not occur in primary fibrinogenolysis.

D-dimer is detected by a latex agglutination test. Latex particles coated with anti-D that bind only to D-dimer are used. These particles will clump when mixed with serum that has an increased level of D-dimer. Since D-dimer levels parallel the amount of fibrinolytic activity in DIC, a quantitative test is often used to evaluate the severity of the disease. The test used is a two-site double antibody sandwich immunoassay.