There are four principal causes of vascular occlusion: (1) extramural compression by fibrosis or a neoplasm, eg, superior vena cava compression by a mediastinal tumor; (2) arterial spasm, which is recognized as a rare cause of ischemia in the brain and myocardium; (3) diseases of the vessel wall, including atherosclerosis and inflammation (vasculitis), which rarely cause occlusion unless complicated by thrombosis; and (4) thrombosis and embolism (see below), which are the most common causes.
Thrombosis is the formation of a solid mass from the constituents of blood (platelets, fibrin, and entrapped red and white blood cells) within the heart or vascular system in a living organism. Thrombosis is usually distinguished from blood clotting, although the distinction is somewhat arbitrary and both invoke the coagulation cascade. Clotting occurs in tissues when blood escapes from an injured vessel (hematoma formation). It also occurs in vessels after death (postmortem clotting of blood) and in vitro (in a test tube outside the body). A thrombus is generally attached to the endothelium and is composed of layers of aggregated platelets and fibrin, whereas a blood clot contains randomly oriented fibrin with entrapped platelets and red cells.
Mechanisms of normal hemostasis. A: In normal uninjured vessels, subendothelial connective tissue, especially collagen and elastin, is not exposed to the circulating blood. B: In the first few seconds after injury, exposure of subendothelial tissue attracts platelets, which adhere and aggregate at the site of injury. Endothelial injury also activates Hageman factor (factor XII), which in turn activates the intrinsic pathway of the coagulation cascade. Release of tissue thromboplastins activates the extrinsic pathway. C: Hemostasis is achieved in minutes. Platelet degranulation stimulates further platelet aggregation. Fibrin formed by activation of the coagulation cascade combines with the mass of aggregated platelets to form the definitive hemostatic plug that seals the injury. Plasmin (fibrinolysin) formed by activation of the fibrinolytic pathway prevents excessive fibrin formation. D: During healing (hours to days), the thrombus retracts, and organization and fibrosis of the thrombus occur. Reendothelialization of the vessels is the final step.
Thrombosis is a normal hemostatic mechanism that acts to stop bleeding when a vessel is injured. Under normal conditions, there is a delicate and dynamic balance between thrombus formation and dissolution of thrombus (fibrinolysis).
Following trauma, the usual initiating factor in thrombus formation is endothelial injury, which leads to formation of a hemostatic platelet plug and activation of the coagulation and fibrinolytic systems.
Formation of Hemostatic Platelet Plug
(Figure 9-14.) Injury to the vascular endothelium exposes subendothelial collagen, which has a strong thrombogenic effect on platelets and results in the adherence of platelets at the site. The platelets adhering to the injured endothelium aggregate to form a hemostatic plug, which is the beginning of a thrombus. Platelet aggregation in turn leads to degranulation of platelets, which releases serotonin, adenosine diphosphate (ADP), adenosine triphosphate (ATP), and thromboplastic substances. ADP—itself a powerful platelet aggregator—causes further accumulation of platelets. The layers of platelets alternating with fibrin in a thrombus appear on microscopic examination as pale lines (lines of Zahn) (Figure 9-15).
Effect of endothelial injury on the coagulation system and platelets, resulting in formation of the definitive hemostatic plug, or thrombus. Note that simultaneous activation of the opposing fibrinolytic system provides a degree of control over the extent of thrombus formation. (For greater detail, see Figure 27-2.)
Thrombus, showing alternating zones of amorphous platelets (lines of Zahn) and fibrillary fibrin.
(Figure 9-14.) Activation of Hageman factor (factor XII in the coagulation cascade) results in the formation of fibrin by activation of the intrinsic coagulation pathway. (For further details, see Chapter 27: Blood: IV. Bleeding Disorders.) Tissue thromboplastins released by injury activate the extrinsic coagulation pathway, which contributes to fibrin formation. Factor XIII acts on fibrin to produce an insoluble fibrillary polymer that—with the platelet plug—makes up the definitive hemostatic plug. Fibrin appears on microscopic examination as a pink-staining fibrillary meshwork intermingled with amorphous pale platelet masses (Figure 9-15).
The normal balance that exists between thrombus formation and fibrinolysis ensures that just the right amount of thrombus is formed in response to endothelial injury so that hemorrhage from the vessel is prevented. Fibrinolytic activity prevents the formation of excessive thrombus. A disturbance of this balance results in abnormal thrombosis or abnormal bleeding.
Excessive thrombus formation results in narrowing or occlusion of the vessel lumen. This usually occurs as a result of local factors at the site that overwhelm the ability of a normally functional fibrinolytic system to prevent excess thrombosis. Decreased fibrinolysis alone almost never produces excessive thrombosis.
In contrast, decreased ability to form thrombi results in excessive bleeding and occurs in a variety of bleeding disorders, including decreased platelets in the blood, deficiency of coagulation factors, and increased fibrinolytic activity. These disorders are considered in Chapter 27: Blood: IV. Bleeding Disorders.
Factors in Thrombus Formation
Endothelial damage, which stimulates both platelet adhesion and activation of the coagulation cascade, is frequently the dominant initiating factor when thrombosis occurs in the arterial circulation. When thrombosis occurs in veins and in the microcirculation, endothelial damage is less conspicuous. Changes in blood flow such as a decreased rate of flow and turbulence, and changes in the blood itself (eg, increased viscosity, increased fibrinogen levels and platelet numbers) are more important factors in venous thrombosis. The entry of thromboplastic substances into the bloodstream may cause widespread thrombosis. Thromboplastic substances are present in some snake venoms, amniotic fluid, the cytoplasmic granules of neutrophil precursors (promyelocytes), and mucin produced by certain cancer cells.
A thrombus is easily recognized as a solid mass in the lumen of a blood vessel that is often attached to the vessel wall (Figure 9-16). Thrombi in the fast-flowing arterial circulation are composed predominantly of fibrin and platelets, with few entrapped erythrocytes—hence the term pale thrombi.
Abdominal aorta, showing multiple large thrombi attached to the endothelial surface. The thrombi have alternating pale and red areas.
Red thrombi are composed of platelets, fibrin, and large numbers of erythrocytes trapped in the fibrin mesh. Red thrombi typically occur in the venous system, where the slower blood flow encourages entrapment of red cells.
Rarely, thrombi composed almost entirely of aggregated platelet masses form in patients who are receiving heparin therapy (the anticoagulant action prevents fibrin formation).
(Figures 9-16 and 9-17.) Arterial thrombosis is common and typically occurs after endothelial damage and local turbulence has been caused by atherosclerosis (Chapter 20: The Blood Vessels). Large- and medium-sized arteries such as the aorta, carotid arteries, arteries of the circle of Willis, coronary arteries, and arteries of the intestine and limbs are mainly affected.
Thrombosis in an athero-sclerotic artery. A: Normal artery, showing typical laminar blood flow. B: Atherosclerotic artery, showing atherosclerotic plaques. The endothelium is intact, but the vessel lumen is narrowed. Decreased blood flow and increased turbulence are present. C: Ulcerated atherosclerotic plaque from which fragments of the plaque have become detached and passed distally as cholesterol emboli (see Figure 9-28). Blood flow is further decreased and turbulence increased. Thrombosis has occurred over the ulcerated area. D: Extension of thrombosis has caused total occlusion of the artery, and there is no blood flow in the vessel.
Less commonly, arterial thrombosis is a complication of arteritis, as occurs in polyarteritis nodosa, giant cell arteritis, thromboangiitis obliterans, and Henoch-Schönlein purpura (Chapter 20: The Blood Vessels). Medium- and small-sized arteries are commonly affected.
Thrombi form within the chambers of the heart in the following circumstances.
Inflammation of Cardiac Valves
Endocardial damage occurring in association with inflammation of the cardiac valves (endocarditis, valvulitis) leads to local turbulence and deposition of platelets and fibrin on the valves. These thrombi are called vegetations (Figure 9-18; Chapter 22: The Heart: II. Endocardium & Cardiac Valves). Vegetations may be large and friable (as occurs in infective endocarditis), and fragments of thrombus often break off and are carried in the circulation as emboli (see below).
Vegetation (= thrombus) on mitral valve in subacute infective endocarditis.
Damage to Mural Endocardium
Myocardial infarction and ventricular aneurysms are associated with damage to the mural endocardium. Thrombi forming on the walls are often large and may also give rise to emboli.
Turbulence and Stasis in Atrial Chambers
Thrombi often form in chambers of the atrium when turbulence and stasis of blood occur, typically in patients with mitral valve stenosis or atrial fibrillation. Thrombi may be so large (ball thrombus) that they obstruct the mitral valve orifice. Fragments of atrial thrombi may become detached and form emboli.
Thrombophlebitis denotes venous thrombosis occurring secondary to acute inflammation of the vein. Thrombophlebitis is a common phenomenon in infected wounds or ulcers and characteristically involves the superficial veins of the extremities. The affected vein is firm and cord-like and shows signs of acute inflammation (pain, redness, warmth, swelling). This type of thrombus tends to be firmly attached to the vessel wall; they rarely form emboli.
Rarely, thrombophlebitis occurs in multiple superficial leg veins (thrombophlebitis migrans) in patients with visceral cancers, most commonly pancreatic and gastric cancer (Trousseau's syndrome). Mucins and other cancer cell products have been shown to possess thromboplastin-like activity.
Phlebothrombosis denotes venous thrombosis occurring in the absence of obvious inflammation. Phlebothrombosis occurs mostly in the deep veins of the leg (deep vein thrombosis). Less commonly, veins of the pelvic venous plexus are involved. Deep vein thrombosis is common and has important medical implications because the large thrombi that form in these veins are only loosely attached to the vessel wall and are often easily detached. They travel in the circulation to the heart and lung and lodge in the pulmonary arteries (pulmonary embolism [Figure 9-19]).
Pulmonary embolism. The pulmonary artery has been opened to reveal a large thromboembolus within it. Note the branching of the embolus, probably corresponding to the configuration of the vein in which it originated.
Up to 50% of patients with deep vein thrombosis show a mutation of the factor V gene, with the result that factor V is less readily degraded by activated protein C. The mutation is known as the Leiden or Q506 mutation (producing a substitution of glycine for arginine at position 506); heterozygous individuals have a tenfold increase in risk for thrombosis, and homozygous individuals a hundredfold increase.
Otherwise, factors causing deep vein thrombosis are those typical of thrombosis in general, although endothelial injury is usually minimal. Sluggish blood flow is an important factor. In the venous plexus of the calf muscles, blood flow is normally maintained by calf muscle contraction (the muscle pump). Prolonged immobilization in bed favors stasis of blood and thrombosis. The routine use of physical therapy, compressive stockings, and early ambulation after surgery has considerably decreased the incidence of postoperative deep vein thrombosis. Other factors predisposing to thrombus formation include changes in the composition of blood in postoperative or postpartum patients that result in an increased tendency toward platelet adhesion and aggregation, as well as increased levels of some coagulation factors (fibrinogen and factors VII and VIII). Oral contraceptives—particularly those with high estrogen levels—may cause increased blood coagulability. Cardiac failure also contributes to sluggish blood flow in the deep veins of the calf. In practice, several of these factors may act together.
Deep vein thrombosis of the legs may cause few or no clinical symptoms. Mild edema of the ankles and calf pain when the ankle is dorsiflexed (Homans' sign) are helpful diagnostic features. In many patients, pulmonary embolism is the first clinical manifestation of phlebothrombosis. Deep vein thrombosis can be detected by venography, ultrasonography, and other radiologic techniques.
Thrombus formation evokes a host response that is designed to remove the thrombus and repair the injured blood vessel. Several outcomes are possible.
Lysis of the thrombus (fibrinolysis) accompanied by reestablishment of the lumen is the ideal end result. The fibrin constituting the thrombus is dissolved by plasmin, which is activated by Hageman factor (factor XII) whenever the intrinsic coagulation pathway is activated (ie, the fibrinolytic system is activated at the same time as the clotting sequence; this mechanism for clot lysis is a built-in control function that normally prevents excessive thrombosis) (Figure 9-14). Fibrinolysis is effective in preventing excess fibrin formation and in dissolving small thrombi. Fibrinolysis is much less effective in dissolving large thrombi occurring in arteries, veins, or the heart itself. Drugs such as streptokinase and tissue plasminogen activator (alteplase, recombinant; tissue plasminogen activator (t-PA)), which activate the fibrinolytic system, are effective when used immediately after thrombosis in causing lysis of the thrombus and reestablishing perfusion. They have been used with some success in the treatment of acute myocardial infarction, deep vein thrombosis, and acute peripheral arterial thrombosis.
Organization and Recanalization
Organization and recanalization commonly occur in large thrombi. Slow liquefaction and phagocytosis of the thrombus are followed by ingrowth of granulation tissue and collagenization (organization). The vessels in the granulation tissue frequently enlarge and may establish new channels across the thrombus (recanalization) (Figure 9-20) through which some blood flow may be restored. Recanalization occurs slowly over several weeks, and although it does not prevent the acute effects of thrombosis, it may slightly improve tissue perfusion over the long term.
Early organization and recanalization of a thrombosed vessel. As the process progresses, the thrombus is completely replaced by collagen and the vascular channels in the granulation tissue dilate.
Sometimes a fragment of thrombus is detached and carried in the circulation to lodge at a distant site—a process termed thromboembolism (see below).
Disseminated Intravascular Coagulation (Dic)
Disseminated intravascular coagulation is the widespread development of small thrombi in the microcirculation throughout the body (Figure 9-21). It is a serious and often fatal complication of numerous diseases and requires early recognition and treatment.
Disseminated intravascular coagulation (DIC). Numerous microthrombi are seen in glomerular capillaries.
Table 9–1. Associated with Disseminated Intravascular Coagulation (DIC). ||Download (.pdf)
Table 9–1. Associated with Disseminated Intravascular Coagulation (DIC).
Disseminated fungal infections
Severe viremias (eg, hemorrhagic fevers)
Plasmodium falciparum malaria
Neonatal and intrauterine infections
Aminotic fluid embolism
Retained dead fetus
Small vessel vasculitides
Surgery with extracorporeal circulation
Snakebite (Russell's viper)
Initiating factors and mechanisms in disseminated intravascular coagulation (DIC). A key difference between DIC and normal thrombus formation is that in DIC both coagulation and fibrinolysis occur diffusely throughout the microcirculation—in contrast to the more localized nature of normal thrombosis. In some instances, thrombosis predominates, resulting in ischemic effects; in others, fibrinolysis predominates, resulting in hemorrhage.
In many cases, the cause of disseminated intravascular coagulation is unknown. Diffuse endothelial injury, as occurs in infections due to gram-negative bacteria (gram-negative sepsis, endotoxic shock), is a common cause. Viral and rickettsial infections may result in direct infection and damage to endothelial cells. Immunologic injury to the endothelium, as occurs in type II and type III hypersensitivity, may also precipitate DIC. Disseminated intravascular coagulation may occur when thromboplastic substances enter the circulation, as occurs in amniotic fluid embolism (amniotic fluid contains thromboplastin, which has procoagulant activity), snakebite (particularly Russell's viper), promyelocytic leukemia (the promyelocytes contain thromboplastic substances), and any condition associated with extensive tissue necrosis.
Decreased Tissue Perfusion
The multiple occlusions of the microcirculation in disseminated intravascular coagulation result in widespread impaired tissue perfusion, leading to shock, accumulation of lactic acid, and microinfarction in many organs. Note that the disseminated thrombi may not be demonstrable at autopsy owing to concurrent fibrinolytic activity (see below).
Disseminated thrombosis also results in the consumption of coagulation factors in the blood (consumption coagulopathy). Paradoxically, thrombocytopenia develops and, together with depletion of fibrinogen and other coagulation factors, leads to abnormal bleeding. This bleeding tendency is aggravated by excessive activation of the fibrinolytic system (activation of Hageman factor XII, which initiates the intrinsic coagulation pathway, also leads to conversion of plasminogen to plasmin). Fibrin degradation products resulting from the action of plasmin on fibrin also have anticoagulant properties, further exacerbating the bleeding tendency. In many patients with disseminated intravascular coagulation, the predominant clinical effect is hemorrhage.
Treatment includes heparin to inhibit the formation of thrombi as well as administration of platelets and plasma to restore the depleted coagulation factors. Monitoring the levels of fibrin degradation products, fibrinogen, and platelets aids diagnosis and assesses the effectiveness of therapy.
Embolism is the occlusion or obstruction of a vessel by an abnormal mass (solid, liquid, or gaseous) transported from a different site by the circulation. Most emboli are detached fragments of thrombi that are carried in the bloodstream to their sites of lodgment (thromboembolism). Numerous other substances serve as less common causes of embolism (Table 9-2).
Types of Embolism.
Types of Embolism.
Origin and Type of Embolism
Circulatory System Involved
Thrombi in right side of heart and systemic veins
Deep vein thrombosis
Circulatory arrest, lung infarction, pulmonary hypertension
Right–sided infective endocarditis
Thrombi in left side of heart and systemic arteries
Cardiac valvular vegetations
Infarction in brain, kidney, intestine, peripheral arteries
Cardiac mural thrombus
Cardiac atrial thrombus
Cardiac aneurysmal thrombus
Aortic aneurysmal thrombus
Puncture of jugular vein
Pulmonary (right ventricle)
Total obstruction of pulmonary flow causes sudden death
Childbirth or abortion
Blood transfusion using positive pressure
Nitrogen gas embolism
Pulmonary and systemic
Ischemia in lung, brain, nerves
Trauma (ie, serious fractures of large bones)
Mostly pulmonary; some fat globules pass to systemic
Microinfarcts and hemorrhages in lung, brain, skin
Bone marrow embolism
No clinical significance
Ulcerated atheromatous plaque
Microinfarction in brain, retina, kidney
Amniotic fluid embolism
Disseminated intravascular coagulation
Depends on location of tumor
The site of embolism is governed by the point of origin and size of the embolus.
Emboli that originate in systemic veins (as a result of venous thrombosis) or in the right side of the heart (eg, infective endocarditis affecting the tricuspid valve) lodge in the pulmonary arterial system unless they are so small (eg, fat globules, tumor cells) that they can pass through the pulmonary capillaries. The point of lodgment in the pulmonary arterial circulation depends on the size of the embolus (see below). Rarely, an embolus originating in a systemic vein passes across a defect in the cardiac interatrial or interventricular septum (thus bypassing the lungs) to lodge in a systemic artery (paradoxic embolism).
Emboli that originate in branches of the portal vein lodge in the liver, eg, cancer cells from colonic or pancreatic cancer.
Origin in Heart and Systemic Arteries
Emboli originating in the left side of the heart and systemic arteries (as a result of cardiac or arterial thrombosis) lodge in a distal systemic artery in sites such as the brain, heart, kidney, extremity, intestine, etc.
Types & Sites of Embolism
Detached fragments of thrombi are the most common cause of clinically significant embolism.
The most serious form of thromboembolism is pulmonary embolism, which may cause sudden death. About 600,000 patients per year develop clinically evident pulmonary embolism in the United States; about 100,000 of them die. Over 90% of pulmonary emboli originate in the deep veins of the leg (phlebothrombosis). More rarely, thrombi in pelvic venous plexuses are the source. Pulmonary embolism is common in the following conditions that predispose to the development of phlebothrombosis: (1) The immediate postoperative period. About 30–50% of patients show evidence of deep vein thrombosis after major surgery. Only a small number of these patients develop clinically significant pulmonary embolism. (2) The immediate postpartum period. (3) Lengthy immobilization in bed. (4) Cardiac failure. (5) Use of oral contraceptives.
(Figure 9-23.) The size of the embolus is the factor most influencing the clinical effects of pulmonary embolism.
Clinical effects of pulmonary embolism. A: Massive pulmonary embolism causes circulatory arrest and sudden death (Figure 9-24). B: A large embolism occluding one pulmonary artery may cause pulmonary infarction or sudden death due to reflex vasoconstriction of the pulmonary circulation (see Figure 9-19). Some healthy individuals may show no ill effects, but this is unusual with a large embolus. C: A small to medium-sized embolus in a pulmonary arterial branch typically has no effect in healthy individuals. Pulmonary infarction may occur if the bronchial circulation is compromised, as in patients with left heart failure and pulmonary hypertension. D: Small emboli have no effect unless they are numerous, in which case they may cause pulmonary hypertension.
Massive pulmonary embolism. The main pulmonary artery has been opened and shows impacted thromboemboli at the orifices of both right and left main pulmonary arteries. This led to sudden death from circulatory obstruction. Note: When the pulmonary arteries were further opened, the emboli were seen to be very large. Only their tips are shown here.
Massive emboli–Large emboli (several centimeters long and of the same diameter as the femoral vein) may lodge in the outflow tract of the right ventricle or in the main pulmonary artery, where they cause circulatory obstruction and sudden death (Figure 9-24). Large emboli lodging in a large branch of the pulmonary artery may also cause sudden death, probably as a result of severe vasoconstriction of the entire pulmonary arterial circulation induced reflexly by lodgment of the embolus (Figure 9-19).
Medium-sized emboli–Moderate-sized emboli often lodge in a major branch of the pulmonary artery. In healthy individuals, the bronchial artery supplies blood (and oxygen) to the lung, and the function of the pulmonary artery is mainly gas exchange (not local tissue oxygenation). In a normal person, therefore, a moderate-sized pulmonary embolus creates an area of lung that is ventilated but not perfused with regard to gas exchange. This results in abnormal gas exchange and hypoxemia, but infarction of the lung does not occur. In a patient with chronic left heart failure or pulmonary vascular disease, however, the bronchial arterial circulation is impaired, and the lung is therefore dependent on the pulmonary artery for perfusion of tissue as well as gas exchange. In these patients, obstruction of a pulmonary artery by a moderate-sized embolus results in pulmonary infarction.
Small emboli–Small emboli lodge in minor branches of the pulmonary artery with no immediate effects (Figure 9-25). In many instances, the emboli either fragment soon after lodgment or dissolve during fibrinolysis, in which case clinical effects are minimal. If numerous small emboli occur over a long period, however, the pulmonary microcirculation may be so severely compromised that pulmonary hypertension results.
Pulmonary thromboembolism partially occluding a small branch of the pulmonary artery in the lung. This has no immediate effect, but pulmonary hypertension may result if recurrent and numerous emboli occur.
Systemic Arterial Embolism
Thromboembolism occurs in systemic arteries when the detached thrombus originates in the left side of the heart or a large artery. Systemic arterial thromboembolism commonly occurs (1) in patients who have infective endocarditis with vegetations on the mitral and aortic valves; (2) in patients who have suffered myocardial infarction in which mural thrombosis has occurred; (3) in patients with mitral stenosis and atrial fibrillation due to left atrial thrombosis; and (4) in patients with aortic and ventricular aneurysms, which often contain mural thrombi. Thromboemboli from any of these locations pass distally to lodge in an artery of some other organ. Because of the anatomy of the aorta, cardiac emboli tend to pass more frequently into the lower extremities or into the circulation derived from the right internal carotid artery than into other systemic arteries.
The clinical effects of systemic thromboembolism are governed by the size of the obstructed vessel, the availability of collateral arterial circulation, and the susceptibility of the tissue to ischemia (see Factors Influencing the Effect of Arterial Obstruction, above). Infarction is common when emboli lodge in the arteries of the brain, heart, kidney, and spleen. Infarction occurs in the intestine and lower extremities only when large arteries are occluded or when the collateral circulation in these tissues is compromised.
Air embolism occurs when enough air bubbles enter the vascular system to produce clinical symptoms; about 150 mL of air causes death. The condition is rare.
Surgery of or Trauma to Internal Jugular Vein
In injuries to the internal jugular vein, the negative pressure in the thorax tends to suck air into the jugular vein. This phenomenon does not occur in injuries to other systemic veins because they are separated by valves from the negative pressure in the chest.
Air embolism may occur during childbirth or abortion, when air may be forced into ruptured placental venous sinuses by the forceful contractions of the uterus.
Air embolism during blood transfusions occurs only if positive pressure is used to transfuse the blood and only if the transfusion is inadvertently not discontinued at its completion. The use of collapsible plastic packs for blood transfusion has greatly reduced the risk of this catastrophe.
When air enters the bloodstream, it passes into the right ventricle, creating a frothy mixture that effectively obstructs the circulation and causes death. More rarely, the frothy air-blood mixture obstructs a pulmonary artery.
Nitrogen Gas Embolism (Decompression Sickness)
Decompression sickness is a form of embolism that occurs in caisson workers and undersea divers if they ascend too rapidly after being submerged for long periods. The disorder is also called the bends or caisson disease (caissons are high-pressure underwater chambers used for deep water construction work). When air is breathed under high underwater pressure, an increased volume of air, mainly oxygen and nitrogen, goes into solution in the blood and equilibrates with the tissues.
If decompression to sea level is too rapid, the gases that have equilibrated in the tissues come out of solution. Oxygen is rapidly absorbed into the blood, but nitrogen gas coming out of solution cannot be absorbed rapidly enough and forms bubbles in the tissues and bloodstream that act as emboli.
Scuba divers breathing high-pressure compressed air who ascend rapidly from depths as shallow as 10 m may also develop decompression sickness, and those who engage in this recreational activity should be taught and cautioned to ascend slowly.
Decompression sickness can also occur in unpressurized aircraft if they ascend too rapidly to high altitudes (above 2000 m). Mountain climbers who climb too rapidly to high altitudes are also at risk.
Platelets adhere to nitrogen gas bubbles in the circulation and activate the coagulation cascade. The resulting disseminated intravascular thrombosis aggravates the ischemic state caused by impaction of gas bubbles in capillaries. Involvement of the brain in severe cases may cause extensive necrosis and death. In less severe cases, nerve and muscle involvement causes severe muscle contractions with intense pain (the bends). Nitrogen gas emboli in the lungs cause severe difficulty in breathing (the chokes) that is associated with alveolar edema and hemorrhage.
Fat embolism occurs when globules of fat enter the bloodstream, typically after fractures of large bones (eg, femur) have exposed the fatty bone marrow. Rarely, extensive injury to subcutaneous adipose tissue causes fat embolism. Although fat globules can be found in the circulation in as many as 90% of patients who have sustained serious fractures, few patients demonstrate clinically significant signs of fat embolism.
Although simple mechanical rupture of fat cells at trauma sites may explain how fat globules can enter the circulation, other factors are probably involved. It has been shown that fat globules enlarge once they are in the circulation, which explains why small globules that bypass lung capillaries may later become obstructed in systemic capillaries. It is thought that release of catecholamines due to the stress of trauma mobilizes free fatty acids, which coalesce to form progressively enlarging fat globules. Adhesion of platelets to fat globules further increases their size and causes thrombosis. When this process is extensive, it is equivalent to disseminated intravascular coagulation.
Circulating fat globules first encounter the capillary network of the lung. Larger fat globules (> 20 μm) are arrested in the lung and cause respiratory distress (dyspnea and abnormal gas exchange). Smaller fat globules escape the lung capillaries and pass into the systemic circulation, where they may obstruct small systemic arteries. Typical clinical features of fat embolism include a hemorrhagic skin rash and brain involvement manifested as acute diffuse neurologic dysfunction.
The possibility of fat embolism must be considered if respiratory distress, cerebral dysfunction, and a hemorrhagic rash occurs 1–3 days after major trauma. The diagnosis can be confirmed by demonstrating fat globules in urine and sputum. About 10% of patients with clinical fat embolism die. At autopsy, fat globules can be demonstrated in many organs using frozen sections and special fat stains (eg, oil red O).
Fragments of bone marrow containing fat and hematopoietic cells may enter the circulation after traumatic injury of bone marrow and may be found in the pulmonary arteries of patients who have suffered rib fractures during cardiopulmonary resuscitative efforts. Bone marrow embolism is of no clinical significance.
Atheromatous (Cholesterol) Embolism
Large ulcerated atheromatous plaques often release cholesterol and other atheromatous material into the circulation (Figure 9-26). Emboli are carried distally to lodge in small systemic arteries. Such embolization in brain produces transient ischemic attacks, characterized by reversible acute episodes of neurologic dysfunction.
Cholesterol embolus derived from an ulcerated atheromatous plaque lodged in a branch of the renal artery.
The contents of the amniotic sac may rarely (1:80,000 pregnancies) enter ruptured uterine venous sinuses during tumultuous labor in childbirth. Although rare, amniotic fluid embolism is associated with a mortality rate of about 80% and is a significant cause of maternal deaths in the United States.
Amniotic fluid is rich in thromboplastic substances that induce disseminated intravascular coagulation, which is the main mechanism by which the disorder is manifested clinically. Amniotic fluid also contains fetal squamous epithelium (desquamated from the skin), fetal hair, fetal fat, mucin, and meconium, all of which may undergo embolization and become lodged in the pulmonary capillaries, a finding that is useful in making an autopsy diagnosis of amniotic fluid embolism (Figure 9-27).
Amniotic fluid embolism of lung.
Cancer cells often enter the circulation during metastasis of malignant tumors (see Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms). Typically, these solitary cells or small clumps of cells are too small to obstruct the vasculature. Occasionally, larger fragments of tumor constitute significant emboli—with renal carcinoma, especially in the inferior vena cava; and with hepatic carcinoma, especially in the hepatic veins.