Dd

P= Plasmin D= D domain E= E domain

DY/YD

nolytic system. PAI-1 is secreted by endothelial cells during injury and suppresses the function of tPA in the plasminogen-plasmin complex. Plasmin as a substrate is directly inhibited by alpha-2-antiplasmin in a 1:1 ratio at the target area. This inhibitor prevents plasmin binding to fibrin in an orderly fashion and claims the role as the most important inhibitor of the fibrinolytic system. Inherited deficiencies of this inhibitor invariably lead to hemorrhagic episodes. Secondary agents that can inhibit fibrinolysis are alpha-2-macroglobulin, C1 inactivator, and alpha-1-antitrypsin. These substances, as protease inhibitors, act upon thrombin formation. Because thrombin is one of the initiators of the generation of plasmin, the secondary effect on the fibrinolytic system is unavoidable.

Measurable Products of the Fibrinolytic System

Physiological fibrinolysis occurs in an orderly fashion, producing measurable products that can be captured by laboratory assays. Specifically, the byproducts of an orderly fibrinolytic system are fibrin split/degradation (FSP/FDP) products composed of fibrin fragments labeled as X, Y, D, and E and the D-dimers, D-D (Fig. 18.3).

The accurate and precise measurement of these products is the basis for therapeutic decisions once pathological clot forming and lysing has been initiated. FSPs/FDPs are formed from plasmin action on fibrin and fibrinogen. As plasmin degrades the fibrinogen molecule, different fragments are split leading to early and late degradation products. Normal levels of FDPs are eliminated through the RES system and usually measure less than 40 pg/mL. Individuals with an intact and operational hemostatic system have normal FDPs. These products are measured semiquantitatively through direct latex agglutination of a thrombin clotted sample. Latex particles are coated with monoclonal antibodies to the human fibrinogen fragments D and E. The test is performed on serum using two dilutions, 1:15 and 1:20. It does not distinguish between fibrinogen and fibrin. Pathological levels of FDPs interfere with thrombin formation and platelet aggregation. Elevated levels may be seen in DIC, pulmonary embolism, obstetrical complications, and other conditions7 (Table 18.1).

Once fibrin has been cross-linked and stabilized by factor XIII, a stable clot has been formed. When this clot is dissolved by plasmin, D-dimers are released. Therefore, D-dimers suggest a breakdown of fibrin clot

Table 18.1 O Conditions That May Elevate Fibrin Degradation Products

• Disseminated intravascular coagulation

• Pulmonary embolism

• Abruptio placentae

• Preeclampsia

• Fetal death in utero

• Postpartum hemorrhage

• Polycystic disease

• Malignancies

• Lupus nephritis

• Thrombolytic therapy and indirectly are an indication that clots have been formed at the site of injury, at the local level. Excess d-dimers are indicative of breakdown of fibrin products within the circulating blood. D-dimers can be assayed semiquantitatively and quantitatively. The semiquantitative assay uses monoclonal antibodies specific for this domain. A simple agglutination test, undiluted patient plasma is mixed with latex solution. Noticeable agglutination is a positive test and indicative of deep vein thrombosis (DVT), pulmonary embolism (PE), or disseminated intravascular coagulation (DIC). Quantitative D-dimer tests are automated and use an enzyme-linked immunosorbent assay (ELISA) procedure. The advantage of this procedure is its ability to detect low levels of D-dimer and to provide specific information as to whether pathological clotting as in DVT or PE has occurred. D-dimers assays have great utility in monitoring thrombolytic therapy.8

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