Pulmonary embolism (TELA) - Causes and pathogenesis

Causes of pulmonary embolism

Deep vein thrombosis of the leg

Deep vein thrombosis of the leg is a very common cause of pulmonary embolism (PE). The annual incidence of deep vein thrombosis of the leg is 100 per 100,000 population. It is often accompanied by an inflammatory process - thrombophlebitis, which significantly increases the risk of developing pulmonary embolism (PE). Thrombosis of the deep and superficial veins of the leg often occurs simultaneously. The spread of the thrombotic process from the superficial and deep veins of the leg to the femoral vein occurs through the great saphenous vein of the thigh. At first, the thrombus has a smaller diameter than the femoral vein, increases mainly in length ("floating thrombus") and does not block the lumen of the vein. Blood flow in the veins is preserved during this period, but the probability of a thrombus fragment breaking off and developing pulmonary embolism (PE) is very high.

The moment when the thrombotic process moves from the deep veins of the legs to the popliteal vein is very dangerous, since the diameter of the thrombus is smaller than the popliteal vein and its fragment can easily penetrate into the inferior vena cava system and further into the pulmonary artery.

Thrombosis in the inferior vena cava system

According to V. B. Yakovlev (1995), thrombosis in the inferior vena cava system is the source of embolism into the pulmonary artery in 83.6% of patients. As a rule, emboli arise from forming (not connected with the vessel wall) thrombi of the popliteal-femoral and femoro-iliac-caval segments. The mobilization of these thrombi and the detachment of a fragment are facilitated by an increase in pressure in the deep venous system (contraction of the muscles of the lower extremities, defecation, tension of the abdominal muscles).

The primary thrombotic process can be localized in the iliac veins (common, external or internal), from which the thrombus fragment then enters the inferior vena cava and then the pulmonary artery.

According to Rich (1994), 50% of cases of deep vein thrombosis of the iliofemoral segment are complicated by pulmonary embolism (PE), while in deep vein thrombosis of the leg - up to 5%.

Inflammatory diseases of the pelvic organs and veins are in some cases complicated by thrombosis and pulmonary embolism (PE).

Cardiovascular diseases

45-50% of patients with pulmonary embolism (PE) have cardiovascular diseases that are extremely predisposing to the development of thrombi and embolism in the pulmonary artery. Such diseases include:

• rheumatism, especially in the active phase, with the presence of mitral stenosis and atrial fibrillation;
• infective endocarditis;
• hypertension;
• ischemic heart disease (usually transmural or subendocardial myocardial infarction);
• severe forms of non-rheumatic myocarditis;
• cardiomyopathy.

In all these situations, pulmonary embolism (PE) occurs when the primary process and, therefore, the source of thromboembolism is localized in the right chambers of the heart and the superior vena cava, which is relatively rare.

Malignant neoplasms

Recurrent thrombophlebitis of the upper and lower extremities is often observed in malignant neoplasms (paraneoplastic syndrome) and can be a source of pulmonary embolism (PE). This most often occurs in pancreatic, lung, and stomach cancer

Generalized septic process

Sepsis in some cases is complicated by thrombosis, which is usually a manifestation of the hypercoagulable phase of the syndrome of disseminated intravascular coagulation. This circumstance can cause pulmonary embolism (PE).

Thrombophilic conditions

Thrombophilic condition is an increased tendency of the body to intravascular thrombosis, which is caused by a violation of the regulatory mechanisms of the hemostasis system. Thrombophilic condition (or "thrombotic disease") can be congenital or acquired.

Congenital thrombophilia is caused by congenital defects in the anticoagulant link of hemostasis or the fibrinolytic system, and often in the blood coagulation system. Genetic disorders predisposing to thrombosis are found in 40-60% of patients with deep vein thrombosis. Congenital thrombophilic conditions include:

• deficiency or qualitative defect of antithrombin-III (the primary anticoagulant, which is a plasma cofactor of heparin and an inhibitor of thrombin, factors Xa, IXa, V, XIa, VIIa, XIIIa);
• deficiency or qualitative defect of the primary anticoagulants proteins C and S (protein C is an inhibitor of coagulation factors VIIIa and Va, accelerates fibrinolysis; protein S, a vitamin K-dependent glycoprotein, stimulates the inactivation of factor Va and VIIIa by protein C); in case of protein C deficiency, thrombosis is caused by the inability to limit the activity of factors V and VIII and fibrin formation. This defect was described in 1981 by Griffin (USA) and is observed in 6-8% of cases of repeated thrombosis, in 3% of patients with primary deep vein thrombosis and in 0.2% of healthy individuals, i.e. 10 times more often than the defect of antithrombin-III (L. I. Patrushev, 1998). Deficiency of protein S also predisposes to thrombosis due to insufficient inhibition of active factors V and VIII. A hereditary predisposition to thrombosis due to protein S deficiency was described in 1984 by Komp and Esmon. This defect occurs in 1-2% of individuals with primary deep vein thrombosis of the leg;
• formation of pathological coagulation factor Va, resistant to the action of activated protein C ("APC-resistance of factor VII"). The defect of factor V consists of a violation of the molecular structure - the replacement of arginine at position 506 of the polypeptide chain with glycine. This hereditary defect is the most common; it is observed in people with primary deep vein thrombosis - in 20%, in people with frequent recurrent thromboses - in 52% of cases, and among the healthy population - in 3-7%;
• heparin cofactor II deficiency. This cofactor was described in 1974 by Briginshaw and Shanberg, isolated in 1981 by Tollefsen. Heparin cofactor II has a pronounced antithrombin effect, is activated by dermatan sulfate on the surface of the vascular endothelium and is a unique system of protection of the vascular bed. With a deficiency of heparin cofactor II, thrombophilia is observed;
• deficiency of plasminogen and its activator;
• fibrinogen structural defect (abnormal polymerization of fibrin prevents its lysis by activated plasminogen); this defect occurs in 0.8% of all thromboses;
• deficiency of coagulation factor XII (Hageman factor) can be a cause of thrombophilia due to dysfunction of the fibrinolysis system;
• prostacyclin deficiency can be congenital or acquired. Prostacyclin is synthesized by the endothelium, has a vasodilating and antiaggregatory effect; with prostacyclin deficiency, a predisposition to increased platelet aggregation and the development of thrombosis is observed;
• increased activity of platelet glycoprotein receptors IIB/IIIA. S. N. Tereshchenko et al. (1998) found the genotype of these receptors P1A1/A2 in the majority of patients with deep vein thrombosis and pulmonary embolism; platelet aggregation and blood clotting increase;
• hyperhomocysteinemia - occurs with a frequency of 1 per 300,000 inhabitants, contributes to increased platelet aggregation and the development of thrombosis. It has been established that high levels of homocysteine in the blood are detected in 19% of patients with juvenile venous thrombosis.

Antiphospholipid syndrome

Antiphospholipid syndrome is a symptom complex based on the development of autoimmune reactions and the appearance of antibodies to phospholipids present on the membranes of platelets, endothelial cells, and nervous tissue. Antiphospholipid syndrome is characterized by an increased tendency to thrombosis of various localizations. This is due to the fact that antiphospholipid antibodies suppress the synthesis of prostacyclin by vascular endothelial cells, stimulate the synthesis of von Willebrand factor, procoagulant activity, inhibit heparin-dependent activation of antithrombin III and heparin-mediated formation of the antithrombin III-thrombin complex, and enhance the synthesis of platelet activating factor. Great importance is attached to the interaction of antiphospholipid antibodies and endothelial cells in the presence of beta2-glycoprotein I. On the one hand, this reduces the activity of beta2-glycoprotein, which has anticoagulant activity, on the other hand, it induces apoptosis (programmed cell death), which, in turn, increases the procoagulant activity of the endothelium. Antiphospholipid antibodies interact with anticoagulant proteins C and S, expressed on the membrane of endothelial cells. All of the above circumstances lead to the formation of venous and arterial thromboses.

Risk factors for pulmonary embolism (PE)

Risk factors predisposing to the development of venous thrombosis and pulmonary embolism:

• prolonged bed rest and heart failure (due to slowing of blood flow and development of venous congestion);
• massive diuretic therapy (excessive diuresis leads to dehydration, an increase in hematocrit and blood viscosity);
• polycythemia and some types of hemoblastoses (due to the high content of red blood cells and platelets in the blood, which leads to hyperaggregation of these cells and the formation of blood clots);
• long-term use of hormonal contraceptives (they increase blood clotting);
• systemic connective tissue diseases and systemic vasculitis (in these diseases, increased blood clotting and platelet aggregation is observed);
• diabetes mellitus;
• hyperlipidemia;
• varicose veins (conditions are created for venous blood stasis and the formation of blood clots);
• nephrotic syndrome;
• permanent central venous catheter;
• strokes and spinal cord injuries;
• malignant neoplasms and chemotherapy for cancer.

Pathogenesis of pulmonary embolism (PE)

According to V. B. Yakovlev (1988), the source of embolism is localized in 64.1% of cases in the veins of the lower extremities, in 15.1% - in the pelvic and iliac veins, in 8.8% - in the cavities of the right heart. The following pathophysiological mechanisms develop in pulmonary embolism.

Acute pulmonary hypertension

A significant increase in pulmonary artery pressure is the most important pathogenetic factor in pulmonary embolism (PE) and is associated with an increase in pulmonary vascular resistance. In turn, high pulmonary vascular resistance is due to the following factors:

• a decrease in the total cross-sectional area and capacity of the pulmonary vascular bed due to obstruction of the pulmonary artery by a thrombus;
• generalized spasm of precapillaries and arterioles in the pulmonary artery system due to alveolar hypoxia and hypoxemia;
• release of serotonin from platelet aggregates in thrombi and emboli; serotonin causes spasm of the pulmonary artery and its branches;
• disturbance in the relationship between endothelial vasodilating and vasoconstrictor factors towards the predominance of the latter. The endothelium produces biologically active substances that regulate vascular tone, including the pulmonary artery - prostacyclin, eudothelial relaxing factor and endothelins.

Prostacyclin is a prostaglandin that is a metabolite of arachidonic acid. It has significant vasodilatory and antiaggregatory effects.

Endothelial relaxing factor is produced by intact endothelium, is nitric oxide (NO), stimulates guanylate cyclase in vascular smooth muscle cells, increases the content of cyclic guanosine monophosphate in them, dilates blood vessels and reduces platelet aggregation.

Endothelins are produced by the vascular endothelium, including the pulmonary endothelium, as well as the bronchial endothelium (Gruppi, 1997) and cause significant vasoconstriction and increased platelet aggregation. In PE, the production of prostacyclin and endothelial relaxing factor decreases, and the synthesis of endothelins is significantly activated, which leads to spasm of the pulmonary artery and its branches and, consequently, to the development of pulmonary hypertension.

Right heart overload

Thromboembolism of large branches of the pulmonary artery is accompanied by a sharp increase in pressure in the pulmonary artery, which creates a significant increase in resistance to the expulsion of blood from the right ventricle. This leads to the development of acute pulmonary heart disease, which can be compensated (without signs of right ventricular failure) or decompensated (acute right ventricular failure).

In case of massive embolism (75% or more), the resistance in the pulmonary artery system increases so significantly that the right ventricle is unable to overcome it and ensure normal cardiac output. This contributes to the development of arterial hypotension (with a simultaneous increase in central venous pressure).

Alveolar hypoxia and arterial hypoxemia

In pulmonary embolism (PE), moderate alveolar hypoxia may develop, which is caused by:

• bronchospasm in the affected area (due to reflex effects on the bronchial muscles, as well as due to the release of bronchospasm mediators - leukotrienes, histamine, serotonin);
• collapse of the respiratory sections of the lung in the pathological focus (due to the lack of perfusion and disruption of the production of alveolar surfactant).

Arterial blood oxygen saturation in pulmonary embolism (PE) is usually reduced, resulting in arterial hypoxemia. It is caused by intrapulmonary shunting of non-oxygenated blood from right to left in the affected area (bypassing the pulmonary artery system), as well as decreased perfusion of lung tissue.

Reflex effects on the cardiovascular system

Pulmonary embolism (PE) causes the development of a number of pathological reflexes that negatively affect the cardiovascular system. These are the pulmonary-coronary reflex (spasm of the coronary arteries), the pulmonary-arterial reflex (dilation of the arteries and a drop in blood pressure, sometimes leading to collapse), and the pulmonary-cardiac reflex (development of severe bradycardia, and in severe cases, even reflex cardiac arrest is possible).

Decreased cardiac output

A decrease in cardiac output largely determines the clinical symptoms of pulmonary embolism (PE). It is caused by mechanical obstruction of the pulmonary vascular bed and the resulting decrease in blood flow to the left ventricle, which is also facilitated by a decrease in the functional reserves of the right ventricle. A reflex drop in arterial pressure also plays a major role in reducing cardiac output.

A decrease in cardiac output is accompanied by a decrease in blood flow in vital organs - the brain, kidneys, as well as in the coronary arteries, and often the development of shock.

Development of pulmonary infarction

According to Moser (1987), pulmonary infarction does not develop often - in less than 10% of cases of pulmonary embolism (PE). Schlant and Alexander (1995) indicate that pulmonary infarction occurs when distal emboli cause complete occlusion of a small-diameter branch of the pulmonary artery. In acute proximal pulmonary embolism, infarction is rare. This is due to the fact that the pulmonary parenchyma is supplied with oxygen from four sources: the airways, pulmonary arteries, collateral blood flow from the bronchial arteries, and reverse diffusion from the pulmonary veins. However, with a preceding regional disorder of blood flow in the bronchial arteries, pulmonary infarction in pulmonary embolism (PE) occurs much more often. Left ventricular failure, mitral stenosis, and chronic obstructive pulmonary diseases also predispose to the development of pulmonary infarction.

A decrease in surfactant production plays an important role in the development of pulmonary infarction.

In pulmonary embolism (PE), fibrinolysis is activated in the first days, and fresh thromboemboli begin to dissolve. This process continues for about 10-14 days. Complete lysis of thrombi in the pulmonary artery occurs within a few weeks. However, not all emboli are lysed - sometimes the thrombus quickly organizes and its lysis becomes impossible. As microcirculation in the lungs improves, surfactant production is restored, which contributes to the rapid disappearance of pathomorphological and clinical manifestations of pulmonary infarction.