Table 5. Main primary physiological anticoagulants
| Anticoagulant name | Action mechanism |
| Antithrombin III (AT III) | Proggressively acting inhibitor of thrombin, Xa factor and, in less extent, other blood coagulation factors. Heparin plasmic co-factor. |
| Heparin | Sulphatated polysaccharide forming complexes with AT III and transforming the latest one into fast-acting anticoagulant. |
| Co-factor of heparin II | Weak anticoagulant the action of which is expressed at heparin presence after AT III removal from plasma |
| Protein C | Vit K-dependent serine-amidase inactivating VIIIa and Va; plasminogen endogenous activator. It is activated by thrombin and complex “thrombomodulin-thrombin” |
| Protein S | Protein C vit K-dependent co-factor |
| Thrombomodulin | Glycoprotein fixated on endothelium cytoplasmic membrane. It binds and inactivates thrombin but does not inhibit its activating action to protein C |
| Tissular coagulation way inhibitor (TCWI or TFPI) | Inhibitor of complex “tissular factor-factor VIIa-factor Xa-Ca++” |
| “Contact inhibitors” (phospholipid, placentary) | They disturb coagulation internal mechanism activation (complexes of XII and XI factors) |
| Antithromboplastines α2-macroglobuline | They are inhibitors of complex III-VIIa. It is weak inhibitor of thrombin, plasmin and kallikrein |
| α1-antitrypsine I | Thrombin, IXa, XIa, XIIa and plasmin inhibitor |
| complement I inhibitor (Anti-C1) | The same |
| Fibrin-monomeres polymerization inhibitors | They inhibit fibrin formation |
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 plasmin (sometimes it is called fibrinolysin), that in a circulation is in non-active state as proenzyme plasminogen. Under the influence of the activators there occurs plasminogen peptide junctions cleavage that leads to in it’s turn to plasmin forming. Plasminogen 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.
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To transform into plasmine plasminogen needs to be activated. Plasminogen activators are contained first of all in tissues (vessel wall). Tissue plasminogen activator (TPA) – is mainly formed in vessel wall endothelium. Urokinase as plasminogen activator is produced in kidneys (juxtaglomerular apparatus), in fibroblastes, epitheliocytes, pneumocytes, placenta, endotheliocytes either. There are also plasminogen 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 percent of antifibrinolytic activity is contained in platelets alpha-granules which are released 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 (б1-antitrypsine) – strong plasmine inhibitor;
4) α2-macroglobulin;
5) plasminogee activator inhibitors secreted by endothelium, macrophages, monocytes and fibroblasts.
Fibrinolysis like the blood coagulation process is performed in three phases.
FIBRINOLYSIS SCHEME:
Internal way External way
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(epinephrine and
norepinephrine level
increasing in blood) Vessels injury
Plasminogen
XII XII
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Plasminogen tis-
sular activator
(PTA)
Urokinase
The others
Plasminogen activators
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(erythrokinase),
leucocytes, platelets
Plasmin
Fibrinogen fibrin
Fibrinogen/fibrin degradation products:
early (A, B, C, X, Y) and late (D, E).
SCHEME 3. Fibrinolysis cascade.
The first phase, the forming and secreting of plasminogen activators may occur in extrinsic and intrinsic ways. The extrinsic way of plasminogen activation is due to the TAP, urokinase and some others. The intrinsic way of plasminogen 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 plasminogen into plasmin. 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”.
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In the second fibrinolysis stage under the action of the activators mentioned above plasminogen transforms into plasmin. Finally, in the third stage, plasmin 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 3rd day of life that leads to fibrin clot dissolving time increasing. Further, natural anticoagulants concentration begins its gradual increasing and becomes normal up to 14th day. Blood fibrinolytic activity reaches its normal value to this time too. But at the same time, antithrombin III concentration is remained comparatively low in a child of the 1st month of life.
Vascular-platelet hemostasis, blood coagulation and fibrinolysis regulation.
There exist 4 levels of haemostatic system regulation.
Molecular level – supposes haemostatic equilibrium supporting for factors influencing on vascular-platelet haemostasis, blood coagulation and fibrinolysis. Factor excess appearing in organism due to one or other reason must be liquidated in short time as soon as possible. Such equillibrium is constantly supported between prostacycline and thromboxanes, procoagulants and anticoagulants, plasminogen activators and inhibitors. Cellular receptors existence to many blood coagulation factors underlies haemostatic equilibrium in haemostatic system at molecular level. Receptors to coagulation and fibrinolysis factors coming off cells (“swimming” receptors) acquire new features becoming natural anticoagulants, plasmin inhibitors and plasminogen activator. Regulational molecular level may be realized with immune system by means of antibodies to activated coagulation and fibrinolysis factors – IIa, Xa, tissular palsminogen activator and others- formation. There is genetic control under factors production providing blood clot forming and dissolving.
Cellular level. In circulation constant coagulational and fibrinolytic factors consumption occurs that must obviousely lead to their concentration restoration. This process must be caused by either activated factors or their metabolic products. If it is really so, cells must have receptors to indicated substances. Such receptors were found on many cells to thrombin, kallikrein, plasminogen activator, plasmin, FDP and others. Cellular level is also provided by “near-wall” fibrinolysis occurring at fibrin accumulation on vascular wall endothelium.
Organic level - determine haemostatic system optimal existential conditions in circulation different regions. Vascular-platelet and coagulational hemostasis and fibrinolysis mosaic is expressed due to this level. Our chair collaborators scientifical works for last years have proved that blood while passing through one or other organs (for example, brain, extremities muscles, kidneys) is satiated with additional hemocoagulational and fibrinolytic factors which may be synthesized in these organs. Moreover, we (V.P.Mischenko, I.V.Mischenko, E.V.Tkachenko, E.A.Tkach, O.V.Kokovskaya, J.M.Grishko and students of different departments and courses which are members of our chair student’s scientific society) demonstrate that blood outflowing from these organs on the right and on the left has different coagulative and fibrinolytic features. It was the base to consider that in animal and human organism there is haemostatic and fibrinolytic process asymmetry. Such an asymmetry was found by us in different laboratory animals (hens, rats, rabbits, guinea pigs, cats) and human beings.
Nervous-humoral regulation controls hemostasis state from molecular till organic level, providing reactions integrity at organism level. It is realized mainly through vegetative nervous system sympathetic and parasympathetic parts.
First of all, one should mention that there exists cortical (conditioned-reflectory) hemostatic system regulation. There some scientific data indicating on the possibility to determine conditioned reflexes both to the acceleration and especially to blood coagulation retardation up to bleedings (bleeded tears, hemorrhagias in places analogous to wounds places, caused at Christ crucifixion et al.).
CNS separate structures (cerebellum, thalamus, hypothalamus) participate in regulation both of activation and inhibition of haemostasis system functionning. As it was proved (B.I.Kuznic, V.P.Mischenko, L.L.Goncharenko., D.S.Zazykina) hypersympathicotony (acute hemorrhagia, hypoxy, stress, intensive muscular activity, adrenalin and noradrenalin introduction) causes blood coagulation acceleration and fibrinolysis enforcement. It is linked not only with Hageman’s factor activation but also with thromboplastin, tissular plasminogen activator releasing from vascular wall. But the most interesting is the fact that at hyperparasympathicotony (vagus irritation, acetylcholine and pilocarpin introduction) we observe coagulation acceleration and fibrinolysis too. Under this conditions thromboplastin and tissular plasminogen activator releasing from vascular wall occurs too. Moreover, drugs vasoconstrictors and vasodilatators by their nature cause similar answer from blood coagulation and fibrinolysis - thromboplastin and tissular plasminogen activator releasing. It testifies that vascular wall is blood coagulation and fibrinolysis efferent regulator!
Hemostasis regulationhumoral mechanism - is hormones, mediators, vitamins and other substances action.
Hormones of suprarenal glands (corticosteroids, adrenalin), hypophysis (ACTH, STH), thyroid (thyroxine), parathyroid (parathormone) and other glands mainly activate blood coagulation, although everything depends on their dosage.
Mediators – noradrenalin, acetylcholine and others mainly activate blood coagulation too.
Vitamins have different influence on hemostasis process.
Vitamin “A” - inhibits coagulation and activates fibrinolysis.
Vitamin “E” – accelerates blood coagulation and suppresses fibrinolysis.
Vitamin “PP” (nicotinic acid) – accelerates coagulation and increases fibrinolysis.
Vitamin “B12” – accelerates coagulation and suppresses fibrinolysis.
Vitamin “C’ - enforces blood coagulation.
But at the same time doctor should remember that this vitamins effect on hemocoagulation depends on their dosage. These data are quite important because vitamins and hormones usage is widely-spread.
Hypercoagulation occurs mainly due to time shortening mainly of the first haemocoagulation stage. That’s why hypercoagulation reasons are quite different and depend on many coagulation factors located in plasma, formed elements and tissues. Hypercoagulation reasons:
1) Hypercoagulation occurs at blood coagulation factors (especially I, VIII and IX) excessment). It may be observed at:
· muscular activity;
· emotions;
· pain;
· hyperadrenalinaemia;
· in pregnant women.
1) Thrombocytosis.
2) Erythrocytosis.
3) Erythrocytic haemolysis:
· burns;
· haemolytic states;
· toxic animals bites;
· blood hemotransfusions.
4) Some leukosis forms.
5) Any tissular injuries.
But hypercoagulation may be transformed into hypocoagulation, which is secondary under natural conditions and is caused by thrombocytes and plasma coagulation factors consumption as well as secondary anticoagulants formation.
Primary hypocoagulation reasons are following:2
1) blood coagulation congenital disorders:
· hemophilia;
· thrombocytopathies (Glanzman’s disease et al.);
2) autoimmune hypocoagulation accompanied by bleedings;
3) DIC-syndrome.
Materials and methods: watery bath, stop-watch, centrifuge, plasma, 1% solution of acetic acid, borate solution, fibrinolysin (plasmin) solution, 0,277% solution of calcium chloride, distillate water, saliva.
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