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Fibrinolytic Testing
Physiology
In healthy subjects, there is a dynamic equilibrium between coagulation and platelets forming a hemostatic plug to close the wound and the fibrinolytic system removing fibrin to prevent vascular occlusion. Fibrinolysis is initiated by the formation of fibrin. Tissue plasminogen activator (tPA) and plasminogen bind to fibrin. Once on the fibrin surface, tPA converts plasminogen into the active enzyme plasmin, which in turn lyses the fibrin, forming fibrin degradation products, including D-dimer. The rate of fibrinolysis is controlled by the concentration of active tPA in blood, which in turn is regulated in three ways:
- 1.
By the rate of endothelial tPA secretion,
- 2.
By the concentration of the tPA inhibitor plasminogen activator inhibitor 1 (PAI-1), and
- 3.
By the rate of hepatic clearance of tPA.
Changes in the relative balance of tPA secretion, inhibition and clearance can lead to alterations in the overall rate of fibrinolysis and clinical risk of bleeding or thrombosis.
Hereditary Fibrinolytic Bleeding
Plasminogen Activator Inhibitor 1 Deficiency
Patients with heterozygous PAI-1 deficiency usually do not have increased bleeding. Patients with homozygous PAI-1 deficiency, resulting in no PAI-1 activity, present with a mild bleeding disorder, including easy bruising, menorrhagia, and moderate to severe delayed bleeding after surgery, often with postoperative wound hematomas. To evaluate draw citrate anticoagulated blood in the morning (PAI-1 peaks in the morning due to a circadian rhythm) with minimal tourniquet time, tourniquets trap tPA secretion in the arm, falsely lowering PAI-1 activity. Patients with PAI-1 deficiency typically show undetectable PAI-1 activity, undetectable or low PAI-1 antigen, and low tPA antigen. It is important to measure tPA antigen and demonstrate a low level to correctly diagnose PAI-1 deficiency. Free tPA in the absence of PAI-1 is cleared faster, leading to lower levels of tPA antigen in patients with PAI-1 deficiency. Low PAI-1 activity with normal or increased tPA antigen is usually due to prolonged application of the tourniquet during blood draw, leading to increased tPA in the sample and falsely low PAI-1 activity.
Antiplasmin Deficiency
Antiplasmin is the primary inhibitor of plasmin. Homozygous antiplasmin deficiency is a rare disorder resulting in moderate to severe bleeding characterized by umbilical stump bleeding, hemarthrosis, easy bruising, gingival bleeding, and bleeding after minor dental or surgical procedures. Only about 20% of patients with heterozygous antiplasmin deficiency typically report bleeding problems, most are asymptomatic. Symptomatic patients typically report mild bleeding similar to that found with PAI-1 deficiency. To evaluate, draw citrate anticoagulated blood and measure antiplasmin activity. Patients with homozygous antiplasmin deficiency have close to undetectable levels of activity, whereas patients with heterozygous deficiency typically have antiplasmin activity levels from 35% to 70% of normal.
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