STUDY - Technical - New Dacian's Medicine
Hemorrhage
and Thrombosis (1)
Translation Draft
Hemorrhage, intravascular thrombosis and embolism are clinical manifestations common to many diseases. Normal hemostasis limits blood loss through precisely regulated interactions between vascular wall components, blood platelets and plasma proteins. However, when a disease or trauma affects large arteries and veins, a massive hemorrhage may occur, although hemostasis mechanisms are normal. Less commonly, bleeding may be caused by an inherited or acquired condition of hemostasis mechanisms. A large number of such clotting deficits have been identified.
In addition, uncontrolled activation of hemostasis mechanisms can cause thrombosis and embolisms, which in turn can decrease blood flow to vital organs such as the brain and myocardium. Although the physiology of thrombosis is less understood than that of hemostasis deficiencies, some groups of patients specifically prone to thrombosis and embolism have been identified. These include patients: 1. immobilized after surgery, 2. those with chronic congestive heart failure, 3. atherosclerosis, 4. neoplasia or 5. during pregnancy. Most of these patients do not show any obvious changes in hemostasis mechanisms. However, there are certain groups of patients who have inherited or acquired a state of "hypercoagulability" or "prethrombotic" that predisposes to recurrent thrombosis.
The essential manifestations of hemostasis disorders, which cause hemorrhages or thrombosis, which are discussed below, along with the clinical approach and evaluation of these patients. Some information on the patient's history, such as how to onset and the location of bleeding, a family history of bleeding or ingestion of past medications, may help to establish a correct diagnosis. Physical examination may identify bleeding in the skin or joint deformities due to previous hemarthrosis. Finally, clotting disorders are diagnosed by laboratory tests.
To arrive at a correct diagnosis, general routine tests are initially used to highlight a systemic condition, then supplemented with specific tests for clotting proteins or platelet function. Patients with hypercoagulability or prethrombotic states may also be identified by careful anamnesis. There are three important elements for diagnosis: 1. repeated episodes of thromboembolism, without an obvious predisposing cause, 2. a family history of thrombosis and 3. thromboembolism occurring in well-documented adolescents and young adults. So far, although several tests are being evaluated, there are no clinically useful screening tests for patients with prethrombotic conditions. However, some of the inherited prethrombotic disorders can be diagnosed through specific immunological and functional investigations.
I will now present some elements about normal hemostasis. The correct diagnosis and treatment of patients with hemorrhage or thrombosis requires knowledge of hemostasis physiology. This process can be divided into a primary and a secondary component, and is initiated when trauma, surgery or other condition destroys the vascular endothelium and blood comes into contact with subendothelial connective tissue. Primary hemostasis is the term that defines the process of formation of platelet thrombuses at the site of the lesion.
This process is initiated seconds after the appearance of the lesion and is of major importance in stopping blood loss from capillaries, small arterioles and venrules. Secondary hemostasis consists of reactions of plasma coagulation systems, which result in the formation of fibrin. It takes a few minutes. The fibrin filaments produced strengthen the initial platelet thrombus. This mechanism is of particular importance in large vessels, as it prevents recurrence of bleeding after a period of hours or days after the initial lesion. Although present here as separate phenomena, primary and secondary hemostasis are closely related. For example, platelet activation accelerates the plasma mechanisms of coagulation, and the products of plasma coagulation reactions, such as thrombin, stimulate platelet activation.
An effective primary hemostasis requires three major factors: platelet adhesiveness, release of granular constituents and platelet aggregation. Within seconds of the lesion, the wafers adhere to the subendothelial collagen fibrils through a specific platelet receptor for collagen, glycoprotein I1/ IIa, which is part of the integrin family. This interaction is stabilized by the von Willebrand factor, an adhesive glycoprotein that allows plaques to remain attached to the vascular wall, despite the strong disruptive forces generated in the vascular lumen. The von Willebrand factor achieves this by creating a link between the platelet receptor on glycoprotein Ib/ IX and the subendothelial collagen fibrils. The plates that have joined then release the preformed granular constituents and generate de novo mediators.
As with other cells, platelet activation and secretion are regulated by changes in cyclic nutrient levels, calcium influx, membrane phospholipid hydrolysis and phosphorylation of essential intracellular proteins. Linking substances with agonistic action, such as epinephrine, collagen or thrombin, to surface platelet receptors activates two membranary enzymes: phospholipase C and phospholipase A2. These enzymes catalyze arachidonic acid from two major membranary phospholipids, phosphatidilinositol and phosphatidylcholine. Initially, a small amount of the released arachidonic acid is converted into thromboxan A2 (TXA2) which in turn can activate phospholipase C.
The formation of TXA2 from arachidonic acid is mediated by the enzyme called cyclooxygenase. This enzyme is inhibited by aspirin and nonsteroidal anti-inflammatory drugs. Inhibition of TXA2 synthesis is a cause of mild bleeding in some patients, as well as the basic mechanism of action of some antithrombotic drugs. Hydrolysis of phospholipid membranary phosphatidilinositol 4,5-biphosphate (PIP2) produces daicil-glycerol (DAG) and inositol triphosphate (IP3), both of which play an essential role in platelet metabolism. IP3 mediates the influx of calcium to platelet cytosol and stimulates phosphoryllation of mild myosin chains.
The latter interact with actin, facilitating the movement of granules and alteration of the platelet shape. DAG activates proteinkinase C which, in turn, phosphorylates different layers including myozinkinase of light chains and a protein of 47000 Yes (plekstrin). Their phosphorylate and other proteins intervene in the regulation of granular secretion of plaques.
The pace and level of platelet activation are controlled by a finely balanced mechanism. TXA2, a platelet product of arachidonic acid, stimulates platelet activation and secretion. In contrast, prostacycline (PGI2), an endothelial derivative of arachidonic acid, inhibits platelet activation by increasing intraplatelet cyclic AMP levels. Similar mechanisms for regulating activation and secretion are found in other cells. After activation, the wafers remove the contents of the granules in the plasma. Endoglycosides and an enzyme that fractionates heparin are released from lysosomes. calcium, serotonin and adenozinfosfat (ADP) are released from dense granules, and several proteins, including von Willebrand factor, fibronectin, thromboplastin, platelet growth factor (FCP) and a protein that neutralizes heparin (platelet factor 4) are released from alpha granules.
After release, ADP binds to a specific purinergic receptor which, after activation, alters the conformation of the glycoprotein complex IIb/ IIIa, so that it binds to fibrinogen, joining adjacent wafers into a hemostatic thrombus. The platelet growth factor stimulates the growth and migration of fibroblasts and smooth muscle cells into the vascular wall, which is an important part of the hemostasis process.
While the primary thrombus is formed, plasma clotting proteins are activated, initiating secondary hemostasis. The coagulation mechanism can be subdivided into a series of reactions that ultimately lead to the production of a sufficient amount of thrombin to convert a small proportion of plasma fibrinogen into fibrin. Each reaction requires the formation of a surface-related complex and the conversion of inactive precursor proteins into active prostheses by limited proteolysis, each of which is regulated by plasma and cellular cofactors as well as calcium.
In the first reaction, the intrinsic or contact phase of coagulation, three plasma proteins, the Hageman factor (factor XII), the high molecular weight kininogen (KGMM) and prekalikrein (PK) form a complex in vascular subendothelial collagen. After binding the KGMN, factor XII is slowly converted into an active protease (XIIa), which then converts both PK to kalikrein and factor XI into active form (XIa). In turn, kalikrein accelerates the transformation of factor XII into active form XIIa, while XIa participates in the following coagulation reactions. Although these interactions are well characterized in vitro, it is possible to have an alternative mechanism for activating factor XI, as patients with factor XII, KGMM or PK deficiency have a seemingly normal hemostasis without clinically evidenced bleeding.
The second reaction provides a secondary way of initiating coagulation by converting factor VII into an active protease. In this pathway, called extrinsic or dependent on tissue factors, a complex is formed between factor VII, calcium and tissue factor, a lipoprotein present in cell membranes that is exposed after their binding. There is growing evidence that the tissue factor-factor VII mechanism is continuously active and has a major contribution to primary coagulation.
Factor VII and three other coagulation proteins (factor II or prothrombin, IX and X) require calcium and vitamin K to be biologically active. These proteins are synthesized in the liver, where there is a vitamin K-dependent carboxylase, which catalyzes a single posttranslational modification that adds a second carboxyl radical to some remnants of glutamic acid. Pairs of these di-gamma-carboxyglutamic acid (G1a) molecules bind calcium, which anchors proteins to negatively charged phospholipid surfaces and gives them biological activity. Inhibition of this posttranslational change by vitamin K antagonists (e.g. warfarin) is the basis of one of the usual forms of anticoagulant therapy.
In the third reaction, the K factor is activated by the proteases generated in the previous reactions. In one of these, a lipid and calcium-dependent complex is formed between factors VIII, IX and X. In this complex, factor IX is first converted to IXa by the XIa factor generated on the intrinsic pathway (reaction I). The X factor is then activated by IXa, and X can be activated by factor VIIa, which was generated on the extrinsic pathway (reaction 2). Activation of factors IX and X is an important connection between the intrinsic and extrinsic mechanism of coagulation.
The fourth, final reaction converts prothrombin into thrombin in the presence of factor V, calcium and phospholipids. Although prothrombin conversion can occur on various natural or artificial surfaces rich in phospholipids, it occurs thousands of times faster on the surface of activated plaques. The product of this reaction, thrombin, has multiple functions in hemostasis. Although its main role is to convert fibrinogen into fibrin, it also activates factors V, VIII and XIII and stimulates platelet aggregation and secretion. Following the release of fibrinopeptides A and B from the alpha and beta chains of fibrinogen, the modified molecule, now called fibrin monomer, is polymerized to form an insoluble gel. The fibrin polymer is then stabilized by cross-linking the fibrin chains by factor XIIIa, a plasma transglutaminase.
Although the classic conception of coagulation presented above is clinically useful, some important elements remain unanswered. Some of these are: 1. why factor XII deficiency produces a dramatic extension of partial thromboplastin time (PTT), but does not cause bleeding, 2. why there is a heterogeneity of bleeding symptoms in patients with factor XI deficiency, 3. why factor VIII or IX deficiencies cause such severe bleeding, even though the extrinsic pathway remains intact... And others...
It is now known that the action of factors IX and X by the tissue factor complex - VIIa plays a major role in the initiation of hemostasis. Once coagulation is initiated through this interaction, a recently discovered protein called the tissue pathway inhibition factor (FTIC) blocks the extrinsic pathway, and elements of the intrinsic pathway, in particular factors VIII and IX, become the main regulators of thrombin formation. This new stage in coagulation would explain why patients with factor XIII deficiency are asymptomatic and why patients with factor XI deficiency have mild to moderate hemorrhagic diathesis.
The lysis of the clot and the restoration of the vascular wall begin immediately after the formation of the permanent thrombus. The fibrinolytic system is activated by three potential factors: 1. Hageman factor fragments, 2. plasminogen (uPA) or urokinase (UK) urinary activator and plasminogen tissue activator (tPA). The main physiological activators tPA and UPA diffuse from endothelial cells and convert the plasminogen absorbed on the surface of the fibrin clot into plasmin.
Subsequently, plasmin degrades the fibrin polymer into small fragments, which are then removed from the monocyto-macrophagic system. Although plasmin can also degrade fibrinogen, the reaction remains localized because: 1. tPA and some forms of EPA activate plasminogen more effectively when it is absorbed on the fibrin clot, 2. circulating plasmin is linked and neutralized by the plasma alpha2 inhibitor (the importance of this factor is underlined by the fact that patients with a deficiency of the plasmin alpha2 inhibitor have uncontrolled fibrinolysis and hemorrhages) and 3. endothelial cells release a lungogen activation inhibitor (PIA-1), which directly blocks the action of tPA.
Thus, as shown above, the plasma coagulation system is finely adjusted, so that only a small amount of each clotting enzyme is converted to its active form. Consequently, the hemostatic thrombus does not extend beyond the site of the lesion. This precise adjustment is important, because in a single millilitre of blood there are enough enzymes to clot in 10-15 seconds all the fibrinogen in the body. Blood fluidity is maintained by its very flow, which reduces the concentration of reactants, the absorption of clotting factors on the surfaces and the presence of multiple plasma inhibitors.
Antithrombin, C and S proteins, as well as FTIC are the most important factors, which, through joint action, maintain blood fluidity.
These inhibitors have different modes of action. Antithrombin forms complexes with all coagulation factors except factor VII. The rate of formation of these complexes is increased by heparin and heparin-like molecules on the surface of endothelial cells. This ability of heparin to increase the activity of antithrombin is the basis of its action as a powerful anticoagulant. Protein C is converted into an active protease by thrombin after it is attached to an endothelial protein called thrombomodulin. Activated protein C causes inactivation of plasma cofactors V and VIII, through a limited proteolysis that slows down two of the important coagulation reactions.
Protein C can also stimulate the release of the plasminogen tissue activator from endothelial cells. The inhibitory function of protein C is amplified by protein S. due to these processes, low levels of antithrombin or proteins C and S, or dysfunctional structures of their molecules lead to hypercoagulability or prethrombotic states. In addition, an inherited defect that is commonly encountered is the presence of a form of factor V (factor V Leiden) resistant to inhibition by protein C. Thus, 20-50% of patients with unexplained venous thromboembolism can needle this defect.
The description of the coagulation mechanisms implies that the process is carried out the same throughout the body. In fact, the process is not uniform and the composition of the clot varies depending on the site of the lesion. Trombies that form in the veins, where the rate of blood flow is reduced, are rich in fibrin and erythrocytes and contain relatively few platelets. They are commonly referred to as red thrombus, due to their appearance on surgical and anatomological examination. The brittle extremities of these red thrombuses, which often form in the veins of the lower limbs, can detach and cause pulmonary embolisms.
The clots formed in the arteries, where the speed of movement is high, are made up predominantly of platelets and have little fibrin. Other white thrombuses can be easily dislodged from the arterial wall and produce distant embolisms with temporary or permanent ischemia. Frequently, embolism occurs in the cerebral and retinal circulation and can cause transient neurological dysfunction (transient ischemic attack), including temporary monocular cetate (fugitive amaurosis), or strokes.
In addition, most episodes of acute myocardial infarction are due to thrombus formed after rupture of atherosclerotic plaques in the affected coronary arteries. It is important to note that there are only small differences between the hemostatic clot, formed as a physiological response to a lesion, and pathological thrombus. To emphasize the similarity, thrombosis has been described as a coagulation occurring at the wrong place or time.
Pfuii, I finished far exceeding my "autonorm" of 1,500 words per post (but it was worth it)... Next time I'll move on to the clinical approach...
Hemorrhage, intravascular thrombosis and embolism are clinical manifestations common to many diseases. Normal hemostasis limits blood loss through precisely regulated interactions between vascular wall components, blood platelets and plasma proteins. However, when a disease or trauma affects large arteries and veins, a massive hemorrhage may occur, although hemostasis mechanisms are normal. Less commonly, bleeding may be caused by an inherited or acquired condition of hemostasis mechanisms. A large number of such clotting deficits have been identified.
In addition, uncontrolled activation of hemostasis mechanisms can cause thrombosis and embolisms, which in turn can decrease blood flow to vital organs such as the brain and myocardium. Although the physiology of thrombosis is less understood than that of hemostasis deficiencies, some groups of patients specifically prone to thrombosis and embolism have been identified. These include patients: 1. immobilized after surgery, 2. those with chronic congestive heart failure, 3. atherosclerosis, 4. neoplasia or 5. during pregnancy. Most of these patients do not show any obvious changes in hemostasis mechanisms. However, there are certain groups of patients who have inherited or acquired a state of "hypercoagulability" or "prethrombotic" that predisposes to recurrent thrombosis.
The essential manifestations of hemostasis disorders, which cause hemorrhages or thrombosis, which are discussed below, along with the clinical approach and evaluation of these patients. Some information on the patient's history, such as how to onset and the location of bleeding, a family history of bleeding or ingestion of past medications, may help to establish a correct diagnosis. Physical examination may identify bleeding in the skin or joint deformities due to previous hemarthrosis. Finally, clotting disorders are diagnosed by laboratory tests.
To arrive at a correct diagnosis, general routine tests are initially used to highlight a systemic condition, then supplemented with specific tests for clotting proteins or platelet function. Patients with hypercoagulability or prethrombotic states may also be identified by careful anamnesis. There are three important elements for diagnosis: 1. repeated episodes of thromboembolism, without an obvious predisposing cause, 2. a family history of thrombosis and 3. thromboembolism occurring in well-documented adolescents and young adults. So far, although several tests are being evaluated, there are no clinically useful screening tests for patients with prethrombotic conditions. However, some of the inherited prethrombotic disorders can be diagnosed through specific immunological and functional investigations.
I will now present some elements about normal hemostasis. The correct diagnosis and treatment of patients with hemorrhage or thrombosis requires knowledge of hemostasis physiology. This process can be divided into a primary and a secondary component, and is initiated when trauma, surgery or other condition destroys the vascular endothelium and blood comes into contact with subendothelial connective tissue. Primary hemostasis is the term that defines the process of formation of platelet thrombuses at the site of the lesion.
This process is initiated seconds after the appearance of the lesion and is of major importance in stopping blood loss from capillaries, small arterioles and venrules. Secondary hemostasis consists of reactions of plasma coagulation systems, which result in the formation of fibrin. It takes a few minutes. The fibrin filaments produced strengthen the initial platelet thrombus. This mechanism is of particular importance in large vessels, as it prevents recurrence of bleeding after a period of hours or days after the initial lesion. Although present here as separate phenomena, primary and secondary hemostasis are closely related. For example, platelet activation accelerates the plasma mechanisms of coagulation, and the products of plasma coagulation reactions, such as thrombin, stimulate platelet activation.
An effective primary hemostasis requires three major factors: platelet adhesiveness, release of granular constituents and platelet aggregation. Within seconds of the lesion, the wafers adhere to the subendothelial collagen fibrils through a specific platelet receptor for collagen, glycoprotein I1/ IIa, which is part of the integrin family. This interaction is stabilized by the von Willebrand factor, an adhesive glycoprotein that allows plaques to remain attached to the vascular wall, despite the strong disruptive forces generated in the vascular lumen. The von Willebrand factor achieves this by creating a link between the platelet receptor on glycoprotein Ib/ IX and the subendothelial collagen fibrils. The plates that have joined then release the preformed granular constituents and generate de novo mediators.
As with other cells, platelet activation and secretion are regulated by changes in cyclic nutrient levels, calcium influx, membrane phospholipid hydrolysis and phosphorylation of essential intracellular proteins. Linking substances with agonistic action, such as epinephrine, collagen or thrombin, to surface platelet receptors activates two membranary enzymes: phospholipase C and phospholipase A2. These enzymes catalyze arachidonic acid from two major membranary phospholipids, phosphatidilinositol and phosphatidylcholine. Initially, a small amount of the released arachidonic acid is converted into thromboxan A2 (TXA2) which in turn can activate phospholipase C.
The formation of TXA2 from arachidonic acid is mediated by the enzyme called cyclooxygenase. This enzyme is inhibited by aspirin and nonsteroidal anti-inflammatory drugs. Inhibition of TXA2 synthesis is a cause of mild bleeding in some patients, as well as the basic mechanism of action of some antithrombotic drugs. Hydrolysis of phospholipid membranary phosphatidilinositol 4,5-biphosphate (PIP2) produces daicil-glycerol (DAG) and inositol triphosphate (IP3), both of which play an essential role in platelet metabolism. IP3 mediates the influx of calcium to platelet cytosol and stimulates phosphoryllation of mild myosin chains.
The latter interact with actin, facilitating the movement of granules and alteration of the platelet shape. DAG activates proteinkinase C which, in turn, phosphorylates different layers including myozinkinase of light chains and a protein of 47000 Yes (plekstrin). Their phosphorylate and other proteins intervene in the regulation of granular secretion of plaques.
The pace and level of platelet activation are controlled by a finely balanced mechanism. TXA2, a platelet product of arachidonic acid, stimulates platelet activation and secretion. In contrast, prostacycline (PGI2), an endothelial derivative of arachidonic acid, inhibits platelet activation by increasing intraplatelet cyclic AMP levels. Similar mechanisms for regulating activation and secretion are found in other cells. After activation, the wafers remove the contents of the granules in the plasma. Endoglycosides and an enzyme that fractionates heparin are released from lysosomes. calcium, serotonin and adenozinfosfat (ADP) are released from dense granules, and several proteins, including von Willebrand factor, fibronectin, thromboplastin, platelet growth factor (FCP) and a protein that neutralizes heparin (platelet factor 4) are released from alpha granules.
After release, ADP binds to a specific purinergic receptor which, after activation, alters the conformation of the glycoprotein complex IIb/ IIIa, so that it binds to fibrinogen, joining adjacent wafers into a hemostatic thrombus. The platelet growth factor stimulates the growth and migration of fibroblasts and smooth muscle cells into the vascular wall, which is an important part of the hemostasis process.
While the primary thrombus is formed, plasma clotting proteins are activated, initiating secondary hemostasis. The coagulation mechanism can be subdivided into a series of reactions that ultimately lead to the production of a sufficient amount of thrombin to convert a small proportion of plasma fibrinogen into fibrin. Each reaction requires the formation of a surface-related complex and the conversion of inactive precursor proteins into active prostheses by limited proteolysis, each of which is regulated by plasma and cellular cofactors as well as calcium.
In the first reaction, the intrinsic or contact phase of coagulation, three plasma proteins, the Hageman factor (factor XII), the high molecular weight kininogen (KGMM) and prekalikrein (PK) form a complex in vascular subendothelial collagen. After binding the KGMN, factor XII is slowly converted into an active protease (XIIa), which then converts both PK to kalikrein and factor XI into active form (XIa). In turn, kalikrein accelerates the transformation of factor XII into active form XIIa, while XIa participates in the following coagulation reactions. Although these interactions are well characterized in vitro, it is possible to have an alternative mechanism for activating factor XI, as patients with factor XII, KGMM or PK deficiency have a seemingly normal hemostasis without clinically evidenced bleeding.
The second reaction provides a secondary way of initiating coagulation by converting factor VII into an active protease. In this pathway, called extrinsic or dependent on tissue factors, a complex is formed between factor VII, calcium and tissue factor, a lipoprotein present in cell membranes that is exposed after their binding. There is growing evidence that the tissue factor-factor VII mechanism is continuously active and has a major contribution to primary coagulation.
Factor VII and three other coagulation proteins (factor II or prothrombin, IX and X) require calcium and vitamin K to be biologically active. These proteins are synthesized in the liver, where there is a vitamin K-dependent carboxylase, which catalyzes a single posttranslational modification that adds a second carboxyl radical to some remnants of glutamic acid. Pairs of these di-gamma-carboxyglutamic acid (G1a) molecules bind calcium, which anchors proteins to negatively charged phospholipid surfaces and gives them biological activity. Inhibition of this posttranslational change by vitamin K antagonists (e.g. warfarin) is the basis of one of the usual forms of anticoagulant therapy.
In the third reaction, the K factor is activated by the proteases generated in the previous reactions. In one of these, a lipid and calcium-dependent complex is formed between factors VIII, IX and X. In this complex, factor IX is first converted to IXa by the XIa factor generated on the intrinsic pathway (reaction I). The X factor is then activated by IXa, and X can be activated by factor VIIa, which was generated on the extrinsic pathway (reaction 2). Activation of factors IX and X is an important connection between the intrinsic and extrinsic mechanism of coagulation.
The fourth, final reaction converts prothrombin into thrombin in the presence of factor V, calcium and phospholipids. Although prothrombin conversion can occur on various natural or artificial surfaces rich in phospholipids, it occurs thousands of times faster on the surface of activated plaques. The product of this reaction, thrombin, has multiple functions in hemostasis. Although its main role is to convert fibrinogen into fibrin, it also activates factors V, VIII and XIII and stimulates platelet aggregation and secretion. Following the release of fibrinopeptides A and B from the alpha and beta chains of fibrinogen, the modified molecule, now called fibrin monomer, is polymerized to form an insoluble gel. The fibrin polymer is then stabilized by cross-linking the fibrin chains by factor XIIIa, a plasma transglutaminase.
Although the classic conception of coagulation presented above is clinically useful, some important elements remain unanswered. Some of these are: 1. why factor XII deficiency produces a dramatic extension of partial thromboplastin time (PTT), but does not cause bleeding, 2. why there is a heterogeneity of bleeding symptoms in patients with factor XI deficiency, 3. why factor VIII or IX deficiencies cause such severe bleeding, even though the extrinsic pathway remains intact... And others...
It is now known that the action of factors IX and X by the tissue factor complex - VIIa plays a major role in the initiation of hemostasis. Once coagulation is initiated through this interaction, a recently discovered protein called the tissue pathway inhibition factor (FTIC) blocks the extrinsic pathway, and elements of the intrinsic pathway, in particular factors VIII and IX, become the main regulators of thrombin formation. This new stage in coagulation would explain why patients with factor XIII deficiency are asymptomatic and why patients with factor XI deficiency have mild to moderate hemorrhagic diathesis.
The lysis of the clot and the restoration of the vascular wall begin immediately after the formation of the permanent thrombus. The fibrinolytic system is activated by three potential factors: 1. Hageman factor fragments, 2. plasminogen (uPA) or urokinase (UK) urinary activator and plasminogen tissue activator (tPA). The main physiological activators tPA and UPA diffuse from endothelial cells and convert the plasminogen absorbed on the surface of the fibrin clot into plasmin.
Subsequently, plasmin degrades the fibrin polymer into small fragments, which are then removed from the monocyto-macrophagic system. Although plasmin can also degrade fibrinogen, the reaction remains localized because: 1. tPA and some forms of EPA activate plasminogen more effectively when it is absorbed on the fibrin clot, 2. circulating plasmin is linked and neutralized by the plasma alpha2 inhibitor (the importance of this factor is underlined by the fact that patients with a deficiency of the plasmin alpha2 inhibitor have uncontrolled fibrinolysis and hemorrhages) and 3. endothelial cells release a lungogen activation inhibitor (PIA-1), which directly blocks the action of tPA.
Thus, as shown above, the plasma coagulation system is finely adjusted, so that only a small amount of each clotting enzyme is converted to its active form. Consequently, the hemostatic thrombus does not extend beyond the site of the lesion. This precise adjustment is important, because in a single millilitre of blood there are enough enzymes to clot in 10-15 seconds all the fibrinogen in the body. Blood fluidity is maintained by its very flow, which reduces the concentration of reactants, the absorption of clotting factors on the surfaces and the presence of multiple plasma inhibitors.
Antithrombin, C and S proteins, as well as FTIC are the most important factors, which, through joint action, maintain blood fluidity.
These inhibitors have different modes of action. Antithrombin forms complexes with all coagulation factors except factor VII. The rate of formation of these complexes is increased by heparin and heparin-like molecules on the surface of endothelial cells. This ability of heparin to increase the activity of antithrombin is the basis of its action as a powerful anticoagulant. Protein C is converted into an active protease by thrombin after it is attached to an endothelial protein called thrombomodulin. Activated protein C causes inactivation of plasma cofactors V and VIII, through a limited proteolysis that slows down two of the important coagulation reactions.
Protein C can also stimulate the release of the plasminogen tissue activator from endothelial cells. The inhibitory function of protein C is amplified by protein S. due to these processes, low levels of antithrombin or proteins C and S, or dysfunctional structures of their molecules lead to hypercoagulability or prethrombotic states. In addition, an inherited defect that is commonly encountered is the presence of a form of factor V (factor V Leiden) resistant to inhibition by protein C. Thus, 20-50% of patients with unexplained venous thromboembolism can needle this defect.
The description of the coagulation mechanisms implies that the process is carried out the same throughout the body. In fact, the process is not uniform and the composition of the clot varies depending on the site of the lesion. Trombies that form in the veins, where the rate of blood flow is reduced, are rich in fibrin and erythrocytes and contain relatively few platelets. They are commonly referred to as red thrombus, due to their appearance on surgical and anatomological examination. The brittle extremities of these red thrombuses, which often form in the veins of the lower limbs, can detach and cause pulmonary embolisms.
The clots formed in the arteries, where the speed of movement is high, are made up predominantly of platelets and have little fibrin. Other white thrombuses can be easily dislodged from the arterial wall and produce distant embolisms with temporary or permanent ischemia. Frequently, embolism occurs in the cerebral and retinal circulation and can cause transient neurological dysfunction (transient ischemic attack), including temporary monocular cetate (fugitive amaurosis), or strokes.
In addition, most episodes of acute myocardial infarction are due to thrombus formed after rupture of atherosclerotic plaques in the affected coronary arteries. It is important to note that there are only small differences between the hemostatic clot, formed as a physiological response to a lesion, and pathological thrombus. To emphasize the similarity, thrombosis has been described as a coagulation occurring at the wrong place or time.
Pfuii, I finished far exceeding my "autonorm" of 1,500 words per post (but it was worth it)... Next time I'll move on to the clinical approach...
Days full of
understanding, love and gratitude!
Dorin, Merticaru