Pulmonary embolism (PE): causes and pathogenesis

Causes of pulmonary embolism

Thigh-deep vein thrombosis

Deep vein thrombosis of the lower leg is a very common cause of pulmonary embolism (PE). The annual incidence of deep vein thrombosis of the lower leg is 100 per 100 000 population. It is often accompanied by an inflammatory process - thrombophlebitis, which significantly increases the risk of pulmonary embolism (PE). There is often a thrombosis of both deep and superficial crural veins. The spread of the thrombotic process from the superficial and deep veins of the shin to the femoral vein occurs through the large subcutaneous vein of the thigh. At first, the thrombus has a diameter smaller than the diameter of the femoral vein, increases mainly in length (the "floating thrombus") and does not block the veins of the vein. Blood flow in the veins is preserved in this period, but the probability of separation of the thrombus fragment and development of pulmonary embolism (PE) is very large.

Very dangerous is the moment when the thrombotic process changes from the deep veins of the lower leg to the popliteal vein, since the diameter of the thrombus is less than the popliteal vein and the fragment can easily enter the system of the inferior vena cava and then into the pulmonary artery.

Thrombosis in the inferior vena cava system

According to VB Yakovlev (1995), thrombosis in the inferior vena cava system is the source of embolism in the pulmonary artery in 83.6% of patients. As a rule, emboli arise from the thrombi of the popliteal-femoral and femoral-ilio-caval segments that form (not connected with the vessel wall). Mobilization of these blood clots and detachment of the fragment is facilitated by increased pressure in the deep vein system (contraction of the muscles of the lower extremities, defecation, tension of the muscles of the abdominal press).

The primary thrombotic process can be localized in the iliac veins (general, external or internal), from which the thrombus fragment then enters the lower hollow vein and then into the pulmonary artery.

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

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

Diseases of the cardiovascular system

In 45-50% of patients with pulmonary embolism (PE), there are diseases of the cardiovascular system, highly predisposing to the development of thrombi and embolism in the pulmonary artery. Such diseases are:

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

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

Malignant neoplasms

Recurrent thrombophlebitis of the upper and lower extremities are often observed in malignant neoplasms (paraneoplastic syndrome) and can be a source of pulmonary embolism (PE). Most often it happens with cancer of the pancreas, lungs, stomach

The generalized septic process

Sepsis in a number of cases is complicated by thrombosis, which is usually a manifestation of the hypercoagulant phase of the syndrome of disseminated intravascular coagulation. This fact 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 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 hemostasis or fibrinolytic system, and also often in the blood coagulation system. In 40-60% of patients with deep vein thrombosis, there are genetic disorders predisposing to thrombosis. Congenital thrombophilic conditions include:

• deficiency or qualitative defect of antithrombin III (primary anticoagulant, plasma cofactor of heparin and thrombin inhibitor, factors Xa, IXa, V, XIa, VIIa, XIIIa);
• deficiency or qualitative defect of primary anticoagulants of proteins C and S (protein C is an inhibitor of coagulation factors VIIIa and Va, accelerates fibrinolysis, protein S, vitamin K-dependent glycoprotein, stimulates the inactivation of factor Va and VIIIa with protein C); with a deficiency of protein C, the cause of thrombosis is the inability to limit the activity of factors V and VIII and fibrinogenesis. 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 subjects, i.e. 10 times more often than the defect of antithrombin-III (LI Patrushev, 1998). Protein S deficiency also predisposes to thrombosis due to insufficient inhibition of active factors V and VIII. Hereditary predisposition to thrombosis as a result of deficiency of protein S was described in 1984 by Comp and Esmon. This defect occurs in 1-2% of patients with primary deep vein thrombosis of the lower leg;
• the formation of the pathological coagulation factor Va, resistant to the action of activated protein C ("APC-resistance of factor VII). The defect of factor V is 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 frequent; it is observed in persons with primary deep vein thrombosis - in 20%, in persons with frequent recurrent thrombosis - in 52% of cases, and among a healthy population - in 3-7%;
• deficiency of cofactor heparin P. This cofactor was described in 1974 by Briginshou and Shanberg, isolated in 1981 by Tollefsen. The cofactor of heparin II has a pronounced antithrombin effect, is activated by dermatan-sulfate on the surface of the vascular endothelium and is a kind of system for protecting the vascular bed. With a deficiency of cofactor heparin II, thrombophilia is observed;
• deficiency of plasminogen and its activator;
• a defect in the structure of fibrinogen (abnormal polymerization of fibrin prevents its lysis by activated plasminogen); this defect occurs in 0.8% of all thrombotic cases;
• Coagulation Factor XII deficiency (Hageman factor) may cause thrombophilia due to impaired function of the fibrinolysis system;
• The deficit of prostacyclin can be congenital or acquired. Prostacyclin is synthesized by endothelium, has a vasodilating and antiaggregation effect; with a deficit of prostacyclin, there is a predisposition to an increase in platelet aggregation and the development of thromboses;
• increased activity of glycoprotein receptors of platelets IIb / IIIa. S.N. Tereshchenko et al. (1998) found the genotype of these P1A1 / A2 receptors in the majority of patients with deep vein thrombosis and PE; aggregation of platelets and coagulability of the blood at the same time increase;
• hyperhomocysteinemia - occurs with a frequency of 1 per 300 000 inhabitants, contributes to an increase in platelet aggregation and the development of thromboses. It was found that a high level of homocysteine in the blood is detected in 19% of patients with juvenile venous thrombosis.

Antiphospholipid syndrome

Antiphospholipid syndrome is a symptom complex, which is based on the development of autoimmune reactions and the appearance of antibodies to phospholipids present on platelet membranes, endothelial cells, and neural tissue. With antiphospholipid syndrome there is an increased tendency to thrombosis of various localizations. This is due to the fact that antiphospholipid antibodies inhibit 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 antithrombin III-thrombin complex, 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, it reduces the activity of beta2-glycoprotein, which has anticoagulant activity, on the other hand - induces apoptosis (programmed cell death), which in turn increases procoagulant activity of the endothelium. Antiphospholipid antibodies interact with anticoagulant proteins C and S, expressed on the membrane of endothelial cells. All the above circumstances lead to the formation of venous and arterial thrombosis.

Risk factors for pulmonary embolism (PE)

Risk factors predisposing to the development of venous thrombosis and PE:

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

Pathogenesis of pulmonary embolism (PE)

According to VB 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. With pulmonary thromboembolism the following pathophysiological mechanisms develop.

Acute pulmonary hypertension

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

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

Prostacyclin is prostaglandin, which is a metabolite of arachidonic acid. It has a significant vasodilator and antiaggregatory effect.

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

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

Overload of the right heart

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

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

Alveolar hypoxia and arterial hypoxemia

With pulmonary embolism (PE), moderate alveolar hypoxia may develop, which is due to:

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

Saturation of arterial blood with oxygen during pulmonary embolism (PE) is usually reduced - arterial hypoxemia develops. It is caused by perigrural pulmonary shunting of non-oxygenated blood from right to left in the affected area (bypassing the pulmonary artery system), as well as by a decrease in the perfusion of lung tissue.

Reflex effects on the cardiovascular system

Thromboembolism of the pulmonary artery (PE) causes a number of pathological reflexes that adversely affect the cardiovascular system. This is a pulmonary-coronary reflex (spasm of the coronary arteries), a pulmonary-arterial reflex (arterial expansion and a drop in blood pressure, sometimes up to collapse), pulmonary cardiac reflex (development of severe bradycardia, in severe cases, even reflex heart failure).

Decreased cardiac output

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

Reduction of 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 a heart attack

According to Moser (1987), lung infarction does not develop often - less than 10% of cases of pulmonary embolism (PE). Schlant and Alexander (1995) indicate that a lung infarct occurs when the distal embolism causes a complete blockage of the small-diameter pulmonary artery branch. In acute proximal pulmonary embolism, infarction is rare. This is due to the fact that pulmonary parenchyma is provided by oxygen from four sources: airways, pulmonary arteries, collateral blood flow from the bronchial arteries, inverse diffusion from the pulmonary veins. However, with the previous regional disturbance of blood flow in the bronchial arteries, pulmonary infarction with pulmonary embolism (PE) occurs significantly more often. The development of lung infarction is also predisposed to left ventricular failure, mitral stenosis, chronic obstructive pulmonary disease.

An important role in the development of lung infarction is played by the reduction of surfactant production.

With pulmonary embolism (PE), fibrinolysis is activated in the early days, and fresh thromboembolism begins to dissolve. This process lasts about 10-14 days. Complete lysis of blood clots in the pulmonary artery occurs within a few weeks. However, not all emboli are lysed - sometimes the thrombus is quickly organized and its lysis becomes impossible. As the microcirculation improves, the products of the surfactant are restored in the lungs, which contributes to the rapid disappearance of pathomorphological and clinical manifestations of a lung infarction.