Fibrinolysis

Fibrinolysis is an enzymatic process by which fibrin and fibrinogen are proteolytically cleaved. It plays a central role in the homeostasis of the coagulation process.

The components of the fibrinolysis system are:

• inactive plasminogen, from which the active plasmin is set, and
• the activators of the plasminogen:
  • t-PA = tissue plasminogen activator or tissue plasminogen activator
  • Urokinase
  • Kallikrein.

The process of fibrinolysis

When clotting begins, fibrinolysis is activated at the same time. The aim is to prevent the coagulation process from spreading throughout the entire vascular system. The fibrin is dissolved again where it has no physiological function or is not needed. A further function of plasmin is to keep the excretory ducts of glands and the urinary tract free of fibrin deposits.

Fibrinolysis is activated by factors at the site of injury when t-PA binds to the fibrin. Factor XIIa cleaves the high-molecular-weight kininogen (HMWK) to bradykinin by releasing peptide fragments. This leads to the release of the tissue-specific plasminogen activator (tPA) from the vascular endothelium. Furthermore, plasma kallikrein activates the plasminogen. It also converts the scu-plasminogen activator, which is not very active, into the highly active tcu-plasminogen activator.

Plasmin in turn activates the F-XII so that feedback is created. Plasmin is a non-specific proteolytic enzyme that not only cleaves fibrin but also degrades fibrinogen, factor V, factor VIII, serum complement and other serum proteins enzymatically. The plasminogen-plasmin system is in turn controlled and slowed down by inhibitors.

The proteolytic degradation of fibrin, and secondarily also the degradation of fibrinogen, produces so-called fibrin cleavage products. These can be detected in the blood. The breakdown products are the so-called fragments X with a molecular weight of 250 kD and the fragments A, B and C. Fragment X produces fragment Y with a molecular weight of 155 kD and fragment D with 83 kD. Fragment Y gives rise to fragment D and fragment E with a molecular weight of 62,000 D. Fragment D is formed by hydrolysis of the cross-linked fibrin.

The D fragments, also called D-dimers, are of great clinical importance. An increase in D-dimers in the blood, which can be detected by D-dimer antibodies using an ELISA, is evidence of an increased course of clotting, which is documented by the opposite reaction of plasmin activity.
The D-dimers have a high diagnostic significance because they can be detected at an increased level when a thrombotic event or pulmonary embolism is suspected. On the other hand, normal D-dimers rule out thrombosis or pulmonary embolism with 95% certainty.

In a large study it could be shown that patients after discontinuing anticoagulation therapy, e.g. after thrombi, have an increased risk of recurrent thrombosis if the D-dimer levels are persistently increased.

Fibrin cleavage products are increased in:

• Thromboembolism
• Consumption coagulopathy
• Sepsis
• Stress
• fibrinolytic therapy
• Leukemias
• Tumours (especially non-small-cell bronchial carcinoma and breast carcinoma)
• hemolytic uremic syndrome
• Polytraumas
• postoperative
• Heart attack
• Inflammations
• chronic inflammatory bowel disease
• severe atherosclerosis.

The degradation products of fibrin are clearly distinguished from the fragments of fibrinogen that lead to fibrin. The concentration of D-dimers in plasma is normally up to 160ug/l.
Fibrinolysis activity is detected not only by the D-dimers but also by the thrombin-antithrombin complex and the prothrombin fragments 1 and 2. Fibrinolysis is also increased in the wake of inflammation, as indicated by the C-reactive protein and the increased fibrin.
In addition to these functions, which help to balance the coagulation system, plasmin also intervenes in complement: it activates the first complement factor, C1. At the same time, the plasmin releases the cleavage product XIIf from factor XIIa, which also activates the complement system. Plasmin is therefore also an immunostimulator. Furthermore, plasmin destroys factors V and VIII.

The fact that the coagulation system can be antagonised was described by Denis as early as 1838, after he was able to bring fibrin back into solution by adding salts. Andral suspected that severe bleeding could be caused by a lack of coagulants. Morawitz discovered in 1906 that the plasma must have a proteolytic activity that cancels out blood clotting. Dastre observed that fibrin is digested when it is mixed with serum. He coined the term fibrinolysis. Jakoby was able to induce fibrinolysis by phosphorus poisoning in dogs.

Plasminogen was first isolated by Deutsch and Mertz in 1970. Another important observation came from Goodpasture, who in 1914 found that plasminogen can be "spontaneously" converted into plasmin, a process that occurs more frequently in liver cirrhosis.

1. HA Neumann (2014) The coagulation system. ABW-Wissenschaftsverlag GmbH Berlin S. 103f.