What is the coagulation process and what is it for
There coagulation it is a process that starts, in certain circumstances, starting from specific elements contained in the blood and which leads to the formation of named protein complexes clots.
Under normal conditions, coagulation is one of the four fundamental moments that make up the hemostasis, which consists of a complex process of stopping bleeding and subsequent revascularization, which allows the repair gods fabrics subjected to trauma.
However, in certain pathological conditions, coagulation can also occur in unnecessary conditions, with consequent possible obstruction of the vascular ducts, or not take place sufficiently to stop the bleeding when necessary: the delicate balance between a state hemorrhagic is one thrombotic it is often difficult to maintain in many pathological conditions.
Notes on the main components of blood
Blood is a body fluid made up of two components, one corpuscular and one plasma, which flows in a pulsatile way within the vascular circulation (arteries, veins and capillaries, both in the systemic and pulmonary circulation).
There are three corpuscles inside the blood: red blood cells (or erythrocytes), white blood cells (or leukocytes) and platelets (or thrombocytes).
Platelets, in particular, contribute to the second phase (for this reason called platelet) of the haemostasis process, after the first phase vascular. Platelets, through their activation and aggregation, lead to the development of an impermeable and irreversible platelet aggregate which leads to a first block of bleeding in the presence of a vascular lesion.
In plasma, that is the blood deprived of the corpuscular part, there are many protein, lipid and even nucleic acid molecules, with just as many functions and clinical meanings.
In addition to these, in the plasma there are all those coagulation and fibrinolysis factors that contribute to the last two phases of the haemostatic process (phase coagulative and phase fibrinolytic). These factors are essentially proteins, for the most part produced by the liver in a constant manner, which allow to stabilize the platelet aggregate and form the thrombus, the ultimate form by which bleeding is stopped.
The factors involved in the coagulation process are twelve in total, in addition to precallicrein (PK) and al high molecular weight kininogen (HMWK). Almost all of them are produced by the liver, with the exception of tissue factor which is synthesized in the endothelium and damaged connective cells.
Clotting factors are activated by contact with molecules present in the connective tissue subendothelial, exposed due to vascular injury, or with the tissue factor which is exposed by endothelial cells in response to tissue damage. In the first case, the intrinsic way, in the second that extrinsic: these two ways then converge in the common way.
Name and main functions
- Fibrinogen (factor I): link between platelets and transformation into fibrin
- Prothrombin (factor II): transformation into thrombin
- Tissue factor (factor III), or tissue thromboplastin: activation of the extrinsic way
- Calcium ions Ca2+ (factor IV): facilitation of the activation of extrinsic way, enzymatic activities and platelet activation and aggregation
- Factor V, or proaccelerin, or labile factor: non-enzymatic cofactor in the activation of prothrombin
- Factor VII, or proconvertin: interaction with tissue factor for the activation of extrinsic way; activation of factor IX (cross - over) of the intrinsic way
- Factor VIII, or anti - haemophilic factor: non-enzymatic cofactor in tenase complex for the activation of the common way; factor VIII is carried by the Von Willebrand factor (vWF), also involved in the hemostatic process
- Factor IX: activation of the tenase complex for the activation of the common way;
- Factor X: conversion of prothrombin to thrombin
- Factor XI: activation of factor IX
- Factor XII, or Hageman factor: interaction with subendothelial proteins for the activation of intrinsic way
- Factor XIII: stabilization of the fibrin clot
- Precallicrein (PK): amplification of the activation of intrinsic way
- High molecular weight kininogen (HWMK): conversion of precallicrein to kallikrein
For coagulation cascade we mean the sequence of activation of the various coagulation factors. This is divided into two ways which, in addition to converging on a common way, present some mechanisms of cross - over, or mutually activating acts to amplify the coagulation efficacy.
For ease of understanding, it may be useful to frame the general events that characterize the waterfall, and then deepen the details later.
A lesion of any origin (traumatic, chemical or biological) can involve, at the level of a vascularized tissue, the structural subversion of the vascular wall, with exposure either of the subendothelial tissue or of the tissue factor by the endothelium itself in reaction to the damage. When this happens, the clotting factors are activated by one or both ways intrinsic ed extrinsic and have as a result, through the activation of the Street common, the conversion of fibrinogen into fibrin. This last molecule, together with the action of the platelets, is the true effector of the formation of the protein aggregate capable of stopping the outflow of blood caused by the lesion.
- Via instrinseca: the pathway originates from the formation of the SPAC complex (plasma system that can be activated by contact), consisting of activated factor XII (FXIIa), activated factor XI (FXIa), kallikrein and high molecular weight kininogen (HMWK). This complex is formed by the reciprocal activation of FXIIa and kallikrein in the presence of the molecules of the subendothelium; FXIIa then binds FXI and HMWK, which join kallikrein and FXIIa itself. This protein system is thus able to activate additional molecules of factor XI; factor XIa, in the presence of calcium ions (FIV), in turn activates factor IX, which is the activator of the first element of the common pathway (FX).
- Extrinsic way: through the interaction of the tissue factor (FIII), calcium ions (FIV) and FVII, a complex is produced that is able to directly activate the FX. This complex also activates further FVII molecules, which form a so-called system tenase complex with the FIXa molecules, Ca ions2+ and phospholipids (the latter exposed on the membranes of platelets and endothelium); the ctenase omlex is a powerful FX activator. Furthermore FXa activates FVII in FVIIa (positive feedback), and the tissue factor system - FVIIa - calcium ions is able to activate FIX.
- Common way: once the FX in FXa is activated, the latter interacts with FVa, calcium ions and phospholipids to give rise to the enzyme prothrombinase or prothrombinase complex. This ultimately determines the activation of prothrombin into thrombin (FIIa), which determines the proteolysis and activation of fibrinogen into fibrin (a fundamental step for the formation of the clot). In addition to this last activity, thrombin is also an activator of many factors upstream of the cascade: it activates or favors the activation of VF, FVIII and FXI.At this point, all the fibrin molecules produced interact with each other. them forming the so-called soft clot of fibrin. This is stabilized and made insoluble (stabilized clot or definitive) through the formation of covalent bonds by FXIIIa, a factor activated by thrombin.
It is important to note that there are numerous interactions between the various coagulation factors, even if they do not belong to the same pathway, and also how often some go to activate the same factors by which they were in turn activated: this has an enormous functional significance, as it greatly amplifies the number of molecules involved in the cascade. Due to this, if there were no coagulation control mechanisms present, 1 ml of plasma would be able to coagulate the entire bloodstream (approximately 5 liters) in just 15 seconds.
Control of coagulation
The control of the coagulation cascade is mainly entrusted to two systems: the presence of the blood flow, capable of rapidly removing and diluting the activated factors, leading them to structures capable of degrading them (liver and monocyte - macrophage system); the presence of broad spectrum inhibitors capable of blocking the proteolytic action of the activated factors.
The main inhibitors are:
antithrombin III (ATIII), which directly binds thrombin, inactivating it;
proteins C and S which, when bound, proteolyze FV and FVIII. Protein C is, among other things, activated by the same thrombin (which therefore has the role of initiating coagulation and simultaneously inhibiting it)
alpha proteins1-antitrypsin, alpha2-macroglobulin and the tissue factor inhibitor.
Defects of haemostasis in the haemorrhagic sense
The presence of bleeding in the absence of traumatic injuries is a problem that can result from defects, congenital or acquired, on various levels.
As described, the hemostatic process consists of four stages, although the first (vascular) it's the last one (fibrinolytic) are not strictly related to the actual blockage of the bleeding. Defects can therefore affect the platelet phase or the coagulation phase.
Defects of the platelet phase of haemostasis
Hemorrhagic manifestations can result from quantitative or qualitative defects of the platelets and factors related to their correct functioning.
As for quantitative defects, an excessively low concentration of platelets in the bloodstream is certainly a factor that favors the onset of bleeding. In addition to platelet concentration, also a quantitative (but also qualitative) deficit of Von Willebrand factor it can lead to similar manifestations, as this protein is involved in platelet haemostasis.
In the case of qualitative defects, on the other hand, they can be of congenital origin (genetically determined), such as alterations at the level of the membrane glycoproteins necessary for binding with the fibrinogen, or of acquired origin. These are far more frequent, and are linked in particular to blood tumor states (myelodysplasias, myeloproliferative syndromes), vitamin C deficiency, uremic syndrome, or to drugs (aspirin, diripidamole, indomethacin, etc.).
Defects of the coagulation phase of haemostasis
The main causes of haemorrhage due to coagulation defect are to be found in coagulopathies (congenital deficiencies of coagulation factors such as haemophilia, liver synthesis deficiency due to liver disease or lack of vitamin K, syndromes CID (disseminated intravascular coagulation), PTT and HUS) and in the use of anticoagulant drugs (warfarin, heparin, new oral anticoagulants), used in many diseases with high prevalence in the population such as atrial fibrillation and the deep vein thrombosis.
Defects in hemostasis in the thrombotic sense
Thrombosis is favored by the three factors of the Virchow triad: endothelial damage, stasis and hypercoagulability.
There are some congenital diseases that determine an increased thrombotic risk, and for which specific screening exists; the most common are the Factor V of Leiden, mutation 20210 of prothrombin, deficiency of antithrombin III, of protein S you hate protein C.
Much more frequent are the acquired forms due to atherosclerotic disease, cancer, the use of the estrogen-progestogen contraceptive pill (for the increase in estrogen levels), obesity and other pathologies such as polycythemia vera, thrombocytosis essential and sickle cell anemia.
Other risk conditions for thrombosis are surgery, especially when followed by long bed rest, and atrial fibrillation.
Tests used to measure thrombotic and hemorrhagic risk
In many pathological conditions it is necessary to measure the quality of the hemostatic process, and this can be done through some laboratory tests:
time of bleeding, or dripping, now almost out of use due to the cruelty and the presence of more reliable tests
time of Quick, or prothrombin (PT), mostly used in its derivative form of IN R (PT of the patient divided by PT of international reference): this test measures the quality of the way extrinsic, and is the most used for monitoring oral anticoagulant therapies (TAO).
Normal PT values are between 10 and 13 seconds, while theIN R in a healthy person it is around 0.8 - 1.2. In anticoagulant therapies, in order to avoid complications in the hemorrhagic sense and in the thrombotic sense, it is necessary to maintain a IN R between 2 and 3.
time of Activated partial thromboplastin (aPTT): measures the quality of the route intrinsic. Normal values are between 28 and 40 seconds, which are maintained 1.5-2 times higher in patients on anticoagulant therapy.