The relative kinetics of clotting and lysis provide a biochemical rationale for the correlation between elevated fibrinogen and cardiovascular disease

Background: Elevated plasma fibrinogen is a well known risk factor for cardiovascular disease. The mechanistic rationale for this is not known.Objectives: These studies were carried out to determine the fibrinogen concentration dependencies of clotting and lysis times and thereby determine whether these times rationalize the correlation between an increased risk of cardiovascular disease and elevated plasma fibrinogen.Methods: The time courses of clot formation and lysis were measured by turbidity in systems comprising a) fibrinogen, thrombin and plasmin, or b) fibrinogen, thrombin, plasminogen and t-PA, or c) plasma, thrombin and t-PA. From the lysis times, k(cat) and K-m values for plasmin action on fibrin were determined.Results: The time to clot increased linearly from 2.9 to 5.6 minutes as the fibrinogen concentration increased from 1 to 9 mu M and did not increase further as the fibrinogen concentration was raised to 20 mu M. In contrast, the clot lysis time increased linearly over the input fibrinogen concentration range of 2 to 20 mu M. A similar linear trend was found in the two systems with t-PA and plasminogen. Apparent K-m and k(cat) values for plasmin were 1.1 +/- 0.6 mu M and 28 +/- 2 min(-1), respectively. K-m values for plasmin in experiments initiated with t-PA and plasminogen were 1.6 +/- 0.2 mu M in the purified system and 2.1 +/- 0.9 mu M in plasma.Conclusion: As the concentration of fibrinogen increases, especially above physiologic level, the balance between fibrinolysis and clotting shifts toward the latter, providing a rationale for the increased risk of cardiovascular disease associated with elevated fibrinogen.