Anticoagulants and fibrinolysis.

Inspite of circulation there are all necessary factors for the clot forming. Under physiological conditions in presence of uninjured vessels a blood remains fluid. It’s determined by the presence of components, preventing the blood coagulation (anticoagulants) in the circulation. Besides, a blood is kept fluid because of the haemostatic system fibrinolytic components in it.

But it’s necessary to underline that blood doesn’t coagulate in vessels due to others reasons too. Factors providing this feature are:

· blood stream velocity: it is well-known that where circulation velocity is the less, the more threat to intravascular blood coagulation (for example, blood is more often condensed in veins comparatively to arteries and phlebothrombosis, thrombophebitis is occured); it also observed in blood circulation regions where circulation is changed, for instance at bifurcations places;

· similar charge (negative) of vascular vessels internal layer;

· formed elements negative charge;

· most coagulational factors negative charge: charge similarity of blood vessels internal layer and blood coagulation factors creates forces for pushing away; at vascular walls injuries vascular wall charge is decreased or even is changed onto positive that creates additional conditions for intravascular coagulation initiating;

· blood coagulation factors are inactive in blood; blood coagulation are not triggered until factors are under unactive state;

· there are inhibitors to active blood coagulation factors (VIII_a, IX_a, X_a, XII_a): even in a case of any factors activation further process development is not obligatory.

Probably, you paid your attention that blood coagulation is origined from XIIth factor activation. It is activated by side surface or hyperadrenalinemia and it becomes XII_a only after this. Reaction cascade (chain) is begun directed to other blood coagulation factors activation. Moreover, this reaction is not spontaneous, it looks like stairs (fall) when one factor activates other one in definite order, in definite sequence.

But anticoagulants are essential factors preventing possible blood coagulation activating.

The natural anticoagulants are divided into primary and secondary ones. The primary anticoagulants are such substances that are constantly present in the circulation. They may be of three groups: antithromboplastines, antithrombines and fibrin forming inhibitors. Otherwise, all these anticoagulants are the substances that act depending on the blood coagulation process stage.

The substances preventing the prothrombinase forming are the antithromboplastines (they are secreted by the vessel wall endothelium, their content in veins is larger than in arteries), vitamin K-dependent protein C (inhibits the factors V, VIII), protein S, the endothelium protein – thrombomodulin, the placenta anticoagulant protein and others.

The substances inhibiting thrombine action are antithrombines. They are of different groups but the most important of them are: antithrombin III and heparin. Antithrombin III – is a prothein of a globulin origin that is formed in liver, kidneys, spleen, lungs and blood vessels as well. Its content reduces with the age, its concentration is less in women as compared with men (NB! Women have the thrombophlebitis and phlebothromboses more often than men), its content in pregnants gets smaller. Its content is smaller in human beings with the II(A) blood group and the people eating fat food (particularly of animal origin). Its activity decreases at the diseases of those organs where it is formed. Antithrombine III is a heparin co-factor. Besides, it inhibits up to 70 per cent of thrombine occuring in blood as well as the factors IXa, Xa, XIa, XIIa. There are cases of its hereditary insufficiency.

Heparin – is also an antithrombine. It is a polysaccharide transforming antithrombine III in anticoagulant of immediate action thus increasing its activity. In absence of antithrombine III heparin possesses a weak anticoagulant activity. Moreover, heparin without antithrombine III doesn’t prevent the external prothrombinase forming way. So, heparin efffect may be very weak as a result of antithrombine level decreasing in patients’ blood that it’s necessary to take into account at its administration. Heparin also forms the complex combinations with thrombogenic protheins and hormones which finally possess anticoagulant and fibrinolytic features. Heparin influences the thrombocyte aggregation, has antiviral action and antiinflammatory properties as well. In blood heparin can be found in basophiles, in vessels – in mast cells. It it degenerated by the heparinase enzyme in liver.

Secondary anticoagulants – are the “worked-off” blood coagulation factors (that participated in blood coagulation process) and degradation fibrin and fibrinogen products or derivates (PDF) having antiaggregative and anticoagulative action. The secondary anticoagulants role comes to limiting of intravascular blood coagulation and thrombus dissemination via vessels.

At various diseases there may appear the pathological anticoagulants dealing with different immunoglobuline classes and inactivating separate blood coagulation factors.

Fibrinolysis – is an integral part of haemostasis system. It always accompanies the process of blood coagulation and even is activated by the same factors (XIIa, kallikrein, HМК and others). Being the important defence reaction it prevents the occlusion of blood vessels by fibrin clots and leads to the vessel recanalization after the bleeding stoppage. The fibrinolysis components play key role in extracellular matrix removal. Besides, they regulate the growth and the division of cells, the reparation of wounds, the regeneration of muscles, the growth and metastasis of tumors etc.

The main enzyme destroying the fibrin is plasmine (sometimes it is called fibrinolysin), that in a circulation is in non-active state as proenzyme plasminogene. Under the influence of the activators there occurs plasminogene peptide junctions cleavage that leads to in it’s turn to plasmine forming. Plasminogene may be found not only in plasma and in serum but in other types of liquids (sperm, follicules, saliva), in tissues and leukocytes either. This is a prothein of a globulin origin the biosynthesis of which is performed in a bone-marrow.

To transform into plasmine plasminogene needs to be activated. Plasminogene activators -are contained first of all in tissues (vessel wall). Tissue plasminogene activator (TPA) – is mainly formed in vessel wall endothelium. Urokinase as plasminogene activator is produced in kidneys (juxtaglomerular apparatus), in fibroblastes, epitheliocytes, pneumocytes, placenta, endotheliocytes either. There are also plasminogene activators in erythrocytes, thrombocytes and leukocytes.

Except plasminogen activators there exist the fibrinolysis inhibitors in plasma.

Nowadays one can tell about 4 types of plasminogen and urokinase tissular activators inhibitors.

1) The most important among them is inhibitor of the first type (ITAP-1), which is often designated as endothelial. Besides, it is synthesized not only by hepatocytes but also by monocytes, macrophages, fibroblasts and myocytes.

Up to 90 per cent of antifibrinolytic activity is contained in platelets alpha-granules which are realeased in blood stream at their activation. While accumulation in endothelium injured locuses platelets release ITAP-1. This reaction has an essential importance for injured vascular wall restoration.

Fibrinolytic blood activity is greatly determined by the correlation between the fibrinolysis activators and inhibitors.

2) α₂-antiplasmine influencing not only on plasmine but also on urokinase;

3) α₁ –protease inhibitor (α₁-antitrypsine) – strong plasmine inhibitor;

4) α₂-macroglobulin;

5) plasminogene activator inhibitors secreted by endothelium, macrophages, monocytes and fibroblasts.

Fibrinolysis like the blood coagulation process is performed in three phases. The first phase, the forming and secreting of plasminogene activators may occur in extrinsic and intrinsic ways. The extrinsic way of plasminogene activation is due to the TAP, urokinase and some others. The intrinsic way of plasminogene activation is divided into Hageman-dependent and Hageman-independent. The first of them takes place under the influence of the XIIa, kallikrein and HMK factors that transform plasminogene into plasmine. Hageman-dependent fibrinolysis is accomplished very fast and bares urgent character. Its main designation comes to the circulation clearence from fibrin clots forming in course of disseminated intravascular blood coagulation process. The second one can be realized under the influence of proteins “C” and “S”.

In the second fibrinolysis stage under the action of the activators mentionned above plasminogen transforms into plasmine. Finally, in the third stage, plasmine effects on fibrin. As a result at first the early (high-molecular) and then the late (low-molecular) fibrin degradation products or derivates (FDP) appear. The early PDF influence on the platelet aggregation and blood coagulation thus increasing them. The late PDF are characterized by the anticoagulant features and effort the fibrinolysis reaction.

Natural ancoagulants and fibrinolytic components level is decreased in new-borns. In low-weighted, immature babies - more expressed anticoagulants decreasing. Fibrinolytic components level is reduced on the 3^rd day of life that leads to fibrin clot dissolving time increasing. Further, natural anticoagulants concentration begins its gradual increasing and becomes normal up to 14^th day. Blood fibrinolytic activity reaches its normal value to this time too. But at the same time, antithrombine III concentration is remainded comparatively low in a child of the 1st month of life.

Lecture 18.