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<< Deep Venous Thrombosis: Identifying The Killer Before It Strikes
Epidemiology, Etiology, And Pathophysiology
Epidemiology
Venous thromboembolism is an important disease process that is encountered by emergency physicians on a regular basis. Deep venous thrombosis affects at least 2 million Americans annually (the diagnosis is also frequently missed), corresponding to nearly 0.1% of the total population. 1 DVT is rarely found in children younger than 15 years, but the incidence of thromboembolic disease (per 1000 patient-years) increases with age — from 1.8 in the age range of 65-69 years, to 3.1 in the 85- to 89-year-old age group.2,3 Furthermore, elderly patients are at special risk for complications, as well as increased mortality.4 Pulmonary embolism (PE), the most-feared consequence of DVT, occurs in an estimated 250,000 to 600,000 individuals per year, and 60,000 to 200,000 die from complications of PE.5 The risk of PE in patients with DVT is difficult to estimate, because of the undetected instances of DVT and PE; data suggest that up to 40% of patients with DVT have clinically silent PE that is later detected by ventilation-perfusion (VQ) scan and chest roentgenogram findings.6 Similarly, autopsy studies indicate that only 20% of pulmonary emboli are ever clinically suspected.7
In the pediatric population, DVT is relatively rare.27 Up to 98% of children diagnosed with DVT or PE have a serious underlying disorder or predisposing factor leading to the thrombosis. The single most common precipitating factor is the presence of indwelling catheters, which are responsible for 21% of all cases.28 Other causes of thrombosis in children include malignancy, major trauma, SLE, surgery, renal disease, oral contraception, inflammatory pulmonary disease, sickle cell anemia, and infection.29
Etiology
Major predisposing factors for DVT include hypercoagulable states, venous stasis, and local damage to the intimal wall of the vein. “Virchow’s triad” is not only of historical importance, but it allows for an intuitive conceptualization of risk factors for DVT. Venous thrombi are often formed in settings where there is low flow, and consequently low shear stress, which allows fibrin strands, red blood cells, and platelets to form a cohesive bond in the valve pockets of calf veins. Alternatively, fibrin, red blood cells, and platelets may form at sites of vessel damage, as may occur after venous access, surgery, or at prior sites of thrombus formation.3 Interestingly, though, while at least 50% of patients with DVT will have risk factors, a substantial percentage will have none.8,9
Hypercoagulable States
Recognized hypercoagulable disorders are too numerous to list. However, the most common and best understood include mutations in factor V, and deficiencies in protein C or protein S. Protein C and its cofactor, protein S, are vitamin K-dependent and work by inhibiting factors V and VIII. When a deficiency of either exists, procoagulation factors are not properly inhibited, resulting in a propensity for development of thrombus. Many patients with a deficiency of either protein C or protein S will have a DVT or PE before age 35.10-12 Activated protein C normally inhibits clotting by cleaving factors Va and VIIIa. The factor V Leiden mutation results in a small change at the cleavage site of activated factor V (Va) that makes it inaccessible to activated protein C. This mutation represents the most common genetic hypercoagulable disorder, with 5-8% of the Caucasian population having a heterozygous trait. Those who are heterozygous for Factor V Leiden have a 7- fold risk for thrombosis, while those who are homozygous have an 80-fold risk.13 This mutation is very uncommon among people of Asian and African descent. Up to 75% of patients with the factor V Leiden mutation will have a thrombotic event before age 50.14 Other, less common genetic causes of hypercoagulability include deficiencies of antithrombin III and hyperhomocysteinemia.
Other conditions that are acquired instead of inherited are also associated with an increased risk of DVT. Autoimmune diseases, such as systemic lupus erythematosus (SLE), are commonly associated with an increased risk of DVT; up to 9% of patients with SLE will develop a DVT at some point. Malignancy is another important risk factor, and spontaneous DVT without an obvious cause is an important flag for possible occult malignancy. While all cancers are associated with a hypercoagulable state, adenocarcinoma of the visceral organs and lung cancer appear to have the highest associations with DVT.15 Further, the treatment of many cancers often includes chemotherapy, and these drugs can affect both the fibrinolytic system and the procoagulant system. There are other drugs that may also cause an increased risk of DVT, including oral estrogens, which have been shown (in case-control studies) to impart a 3- to 12-fold relative risk increase for thrombosis, compared to women who were not taking oral contraceptives or hormone replacement therapy.16
Polycythemia increases the risk for DVT, and this risk is linearly associated with the increased hematocrit. While more deaths occur from arterial thrombosis, up to 13% of polycythemia-related deaths are due to venous thromboembolic disease. Regarding the hematocrit, though it is decreased due to hemodilution during pregnancy, pregnancy is still associated with an increased the risk of DVT and PE. In fact, PE is the most common, nontraumatic cause of maternal death during pregnancy and the postpartum period. The incidence of DVT in the postpartum period ranges from 0.61 to 20 cases per 1000 peripartum months.16
Obesity has been thought in the past to be a unique risk factor for DVT. However, when other risk factors are taken into account in this patient population, there is mixed evidence that obesity alone is an independent risk factor.16 Research continues in this field, and at the very least obesity is associated with DVT.9 Obesity also appears to affect the progression of disease: a recent case-controlled study of 23,796 autopsies did find a strong correlation between subcutaneous fat accumulation and BMI and the risk for PE in patients with proximal deep vein thrombosis.140 The association between obesity and DVT must clearly be kept in mind by clinicians.
Smoking tobacco products has also been associated with an increased risk of venous thromboembolism. Patients, especially those with any of the other major risk factors, should certainly be educated about the connection, since smoking is one of the few risks that can be modified directly by the patient.
Venous Stasis
A reduction in venous flow due to immobility, local pressure, shock, congestive heart failure, or venous obstruction predisposes to venous thromboembolism. While there is a clear association between the incidence of DVT and the systemic venous pooling seen in right-sided heart failure, there are other conditions causing venous stasis that do not have as much association as once thought.17 Of particular interest to the wider community, anecdotal news reports of DVTs following prolonged air travel gave rise to the popular term “economy class syndrome.”18 A recent study of 116 travelers screened for asymptomatic DVT following a “long haul” flight found that 12 (10%; 95% confidence interval [CI], 6%-17%) had calf DVTs, but none had proximal extension.19 The public concern has turned out to have little basis, when evaluated with scientific rigor. The Air Transport Medicine Committee of the Aerospace Medical Association’s consensus paper states that “current evidence indicates that any association between symptomatic DVT and travel by air is weak, and the incidence is less than the impression given by recent publicity.”20
Intimal Damage
Local damage to the intimal wall of a vein can occur because of inflammation, infection, local trauma, or indwelling catheters. However, vessel wall damage is less important in venous thrombosis formation than in arterial thrombosis formation. Examples of low-grade, chronic vessel injury that increase the baseline propensity for thrombosis may include endothelial injury due to chemotherapy, hyperhomocysteinemia, vasculitis, or antiphospholipid syndrome. Perhaps the greatest risk factor for venous thrombosis is prior thromboembolic disease.21,22 This may be due to prior vessel wall injury combined with factors, such as hypercoagulability, which formed the first DVT.
Major surgery and multisystem trauma often entail 2 or more classic risk factors for DVT (eg, activation of clotting factors, immobility, local damage), and together they are responsible for up to 40% of all thromboembolic disease. The rate of postoperative DVT in nonanticoagulated patients is 70% after nonelective hip surgery, 48% after elective orthopedic surgery, and 12% after elective general surgery. Approximately one fifth of the cases of postoperative DVT cause a clinically apparent PE, and approximately one third of these are fatal. Despite prophylactic heparin, 5 to 10% of postoperative orthopedic patients develop a PE.9,16
Upper extremity DVT is far less common than lower extremity DVT and is most often associated with the presence of a central venous line. The subclavian vein is the most common place to develop upper extremity DVT, followed by the axillary and brachial veins.23-25 Compressive trauma (eg, hanging upside down in an overturned vehicle with a shoulder harness still on, or overdosing on heroin and passing out with the arm extended) is still a significant cause of subclavian DVT. Effort thrombosis is a syndrome of DVT unique to the upper extremity, typically occurring in young males after strenuous or unusual exercise.26
Pathophysiology
Lower extremity DVTs arise most often in the deep veins of the calf musculature.30 The plexus of multiple branching veins just distal to the popliteal vein behind the knee favors thrombosis, due to a tendency for venous stasis with immobility.31 Once formed, thrombus may progress from the distal to a more proximal vein of the lower extremity. The common femoral vein drains into the external iliac vein. Going in a reverse direction, proximal to distal, the common femoral vein splits into the deep and superficial femoral veins, both of which are deep veins. The deep femoral vein dives into the thigh, while the superficial femoral vein takes an anterior-medial course in the thigh, and then dives deep, to appear again in the popliteal fossa before trifurcating into the calf veins. It is important to be aware of deep vein locations when performing the physical examination; for instance, tenderness located over the anterior tibia would not be suspicious for DVT.
Once a DVT has formed, it begins to organize. As the formation progresses more proximally, the patient may begin to be symptomatic, due to venous obstruction or perivascular inflammation. Symptoms can progress over hours and may include pain, swelling, tenderness along the deep leg vein distribution, erythema, or even cyanosis. However, many patients may have minimal symptoms, or perhaps only one out of the more typical symptoms listed. It is important to note that low-grade fever is occasionally associated with DVT, but this rarely exceeds 100.4°F (38°C). In contrast, high fevers are seen in the septic thrombophlebitis associated with IV drug use.32-37 It is also important to note that, even when classic symptoms are present, only about a quarter of patients presenting with such symptoms have DVT on imaging.38
Leg pain can start within hours of DVT inception. The pain associated with DVT depends largely on the extent of thrombosis and resulting obstruction and inflammation. Significant pain that travels to the groin will likely not occur until the DVT has propagated proximally, and the amount of time this takes can vary greatly from patient to patient. Propagation to the groin does not occur at all in some. Pain along the deep venous distribution is not uncommon. Leg swelling may or may not be present. Palpable cords may signal superficial thrombophlebitis, but their absence does not exclude the presence of DVT. Patients presenting with concomitant shortness of breath or chest pain may have a PE.
It is generally thought that DVT involves the proximal deep veins prior to embolization. Free-floating clot ends, as visualized on ultrasound, are at the highest risk for embolization. However, calf vein DVTs are thought to embolize occasionally, although it is difficult to prove that calf DVTs may not progress to the proximal system prior to embolization. Superficial venous thrombi must progress to the deep system prior to embolizing.40
As a thrombus ages, it also hardens. This organization results from a change in the makeup of a thrombus from mostly platelets to predominantly crosslinked fibrin.41 Hence, as the thrombus ages, it becomes less likely to embolize to the lungs.41 The probability of embolization decreases about 5-10 days after formation, due to the polymerization of fibrin strands.
Venous thromboembolism is an important disease process that is encountered by emergency physicians on a regular basis. Deep venous thrombosis affects at least 2 million Americans annually (the diagnosis is also frequently missed), corresponding to nearly 0.1% of the total population. 1 DVT is rarely found in children younger than 15 years, but the incidence of thromboembolic disease (per 1000 patient-years) increases with age — from 1.8 in the age range of 65-69 years, to 3.1 in the 85- to 89-year-old age group.2,3 Furthermore, elderly patients are at special risk for complications, as well as increased mortality.4 Pulmonary embolism (PE), the most-feared consequence of DVT, occurs in an estimated 250,000 to 600,000 individuals per year, and 60,000 to 200,000 die from complications of PE.5 The risk of PE in patients with DVT is difficult to estimate, because of the undetected instances of DVT and PE; data suggest that up to 40% of patients with DVT have clinically silent PE that is later detected by ventilation-perfusion (VQ) scan and chest roentgenogram findings.6 Similarly, autopsy studies indicate that only 20% of pulmonary emboli are ever clinically suspected.7
In the pediatric population, DVT is relatively rare.27 Up to 98% of children diagnosed with DVT or PE have a serious underlying disorder or predisposing factor leading to the thrombosis. The single most common precipitating factor is the presence of indwelling catheters, which are responsible for 21% of all cases.28 Other causes of thrombosis in children include malignancy, major trauma, SLE, surgery, renal disease, oral contraception, inflammatory pulmonary disease, sickle cell anemia, and infection.29
Etiology
Major predisposing factors for DVT include hypercoagulable states, venous stasis, and local damage to the intimal wall of the vein. “Virchow’s triad” is not only of historical importance, but it allows for an intuitive conceptualization of risk factors for DVT. Venous thrombi are often formed in settings where there is low flow, and consequently low shear stress, which allows fibrin strands, red blood cells, and platelets to form a cohesive bond in the valve pockets of calf veins. Alternatively, fibrin, red blood cells, and platelets may form at sites of vessel damage, as may occur after venous access, surgery, or at prior sites of thrombus formation.3 Interestingly, though, while at least 50% of patients with DVT will have risk factors, a substantial percentage will have none.8,9
Hypercoagulable States
Recognized hypercoagulable disorders are too numerous to list. However, the most common and best understood include mutations in factor V, and deficiencies in protein C or protein S. Protein C and its cofactor, protein S, are vitamin K-dependent and work by inhibiting factors V and VIII. When a deficiency of either exists, procoagulation factors are not properly inhibited, resulting in a propensity for development of thrombus. Many patients with a deficiency of either protein C or protein S will have a DVT or PE before age 35.10-12 Activated protein C normally inhibits clotting by cleaving factors Va and VIIIa. The factor V Leiden mutation results in a small change at the cleavage site of activated factor V (Va) that makes it inaccessible to activated protein C. This mutation represents the most common genetic hypercoagulable disorder, with 5-8% of the Caucasian population having a heterozygous trait. Those who are heterozygous for Factor V Leiden have a 7- fold risk for thrombosis, while those who are homozygous have an 80-fold risk.13 This mutation is very uncommon among people of Asian and African descent. Up to 75% of patients with the factor V Leiden mutation will have a thrombotic event before age 50.14 Other, less common genetic causes of hypercoagulability include deficiencies of antithrombin III and hyperhomocysteinemia.
Other conditions that are acquired instead of inherited are also associated with an increased risk of DVT. Autoimmune diseases, such as systemic lupus erythematosus (SLE), are commonly associated with an increased risk of DVT; up to 9% of patients with SLE will develop a DVT at some point. Malignancy is another important risk factor, and spontaneous DVT without an obvious cause is an important flag for possible occult malignancy. While all cancers are associated with a hypercoagulable state, adenocarcinoma of the visceral organs and lung cancer appear to have the highest associations with DVT.15 Further, the treatment of many cancers often includes chemotherapy, and these drugs can affect both the fibrinolytic system and the procoagulant system. There are other drugs that may also cause an increased risk of DVT, including oral estrogens, which have been shown (in case-control studies) to impart a 3- to 12-fold relative risk increase for thrombosis, compared to women who were not taking oral contraceptives or hormone replacement therapy.16
Polycythemia increases the risk for DVT, and this risk is linearly associated with the increased hematocrit. While more deaths occur from arterial thrombosis, up to 13% of polycythemia-related deaths are due to venous thromboembolic disease. Regarding the hematocrit, though it is decreased due to hemodilution during pregnancy, pregnancy is still associated with an increased the risk of DVT and PE. In fact, PE is the most common, nontraumatic cause of maternal death during pregnancy and the postpartum period. The incidence of DVT in the postpartum period ranges from 0.61 to 20 cases per 1000 peripartum months.16
Obesity has been thought in the past to be a unique risk factor for DVT. However, when other risk factors are taken into account in this patient population, there is mixed evidence that obesity alone is an independent risk factor.16 Research continues in this field, and at the very least obesity is associated with DVT.9 Obesity also appears to affect the progression of disease: a recent case-controlled study of 23,796 autopsies did find a strong correlation between subcutaneous fat accumulation and BMI and the risk for PE in patients with proximal deep vein thrombosis.140 The association between obesity and DVT must clearly be kept in mind by clinicians.
Smoking tobacco products has also been associated with an increased risk of venous thromboembolism. Patients, especially those with any of the other major risk factors, should certainly be educated about the connection, since smoking is one of the few risks that can be modified directly by the patient.
Venous Stasis
A reduction in venous flow due to immobility, local pressure, shock, congestive heart failure, or venous obstruction predisposes to venous thromboembolism. While there is a clear association between the incidence of DVT and the systemic venous pooling seen in right-sided heart failure, there are other conditions causing venous stasis that do not have as much association as once thought.17 Of particular interest to the wider community, anecdotal news reports of DVTs following prolonged air travel gave rise to the popular term “economy class syndrome.”18 A recent study of 116 travelers screened for asymptomatic DVT following a “long haul” flight found that 12 (10%; 95% confidence interval [CI], 6%-17%) had calf DVTs, but none had proximal extension.19 The public concern has turned out to have little basis, when evaluated with scientific rigor. The Air Transport Medicine Committee of the Aerospace Medical Association’s consensus paper states that “current evidence indicates that any association between symptomatic DVT and travel by air is weak, and the incidence is less than the impression given by recent publicity.”20
Intimal Damage
Local damage to the intimal wall of a vein can occur because of inflammation, infection, local trauma, or indwelling catheters. However, vessel wall damage is less important in venous thrombosis formation than in arterial thrombosis formation. Examples of low-grade, chronic vessel injury that increase the baseline propensity for thrombosis may include endothelial injury due to chemotherapy, hyperhomocysteinemia, vasculitis, or antiphospholipid syndrome. Perhaps the greatest risk factor for venous thrombosis is prior thromboembolic disease.21,22 This may be due to prior vessel wall injury combined with factors, such as hypercoagulability, which formed the first DVT.
Major surgery and multisystem trauma often entail 2 or more classic risk factors for DVT (eg, activation of clotting factors, immobility, local damage), and together they are responsible for up to 40% of all thromboembolic disease. The rate of postoperative DVT in nonanticoagulated patients is 70% after nonelective hip surgery, 48% after elective orthopedic surgery, and 12% after elective general surgery. Approximately one fifth of the cases of postoperative DVT cause a clinically apparent PE, and approximately one third of these are fatal. Despite prophylactic heparin, 5 to 10% of postoperative orthopedic patients develop a PE.9,16
Upper extremity DVT is far less common than lower extremity DVT and is most often associated with the presence of a central venous line. The subclavian vein is the most common place to develop upper extremity DVT, followed by the axillary and brachial veins.23-25 Compressive trauma (eg, hanging upside down in an overturned vehicle with a shoulder harness still on, or overdosing on heroin and passing out with the arm extended) is still a significant cause of subclavian DVT. Effort thrombosis is a syndrome of DVT unique to the upper extremity, typically occurring in young males after strenuous or unusual exercise.26
Pathophysiology
Lower extremity DVTs arise most often in the deep veins of the calf musculature.30 The plexus of multiple branching veins just distal to the popliteal vein behind the knee favors thrombosis, due to a tendency for venous stasis with immobility.31 Once formed, thrombus may progress from the distal to a more proximal vein of the lower extremity. The common femoral vein drains into the external iliac vein. Going in a reverse direction, proximal to distal, the common femoral vein splits into the deep and superficial femoral veins, both of which are deep veins. The deep femoral vein dives into the thigh, while the superficial femoral vein takes an anterior-medial course in the thigh, and then dives deep, to appear again in the popliteal fossa before trifurcating into the calf veins. It is important to be aware of deep vein locations when performing the physical examination; for instance, tenderness located over the anterior tibia would not be suspicious for DVT.
Once a DVT has formed, it begins to organize. As the formation progresses more proximally, the patient may begin to be symptomatic, due to venous obstruction or perivascular inflammation. Symptoms can progress over hours and may include pain, swelling, tenderness along the deep leg vein distribution, erythema, or even cyanosis. However, many patients may have minimal symptoms, or perhaps only one out of the more typical symptoms listed. It is important to note that low-grade fever is occasionally associated with DVT, but this rarely exceeds 100.4°F (38°C). In contrast, high fevers are seen in the septic thrombophlebitis associated with IV drug use.32-37 It is also important to note that, even when classic symptoms are present, only about a quarter of patients presenting with such symptoms have DVT on imaging.38
Leg pain can start within hours of DVT inception. The pain associated with DVT depends largely on the extent of thrombosis and resulting obstruction and inflammation. Significant pain that travels to the groin will likely not occur until the DVT has propagated proximally, and the amount of time this takes can vary greatly from patient to patient. Propagation to the groin does not occur at all in some. Pain along the deep venous distribution is not uncommon. Leg swelling may or may not be present. Palpable cords may signal superficial thrombophlebitis, but their absence does not exclude the presence of DVT. Patients presenting with concomitant shortness of breath or chest pain may have a PE.
It is generally thought that DVT involves the proximal deep veins prior to embolization. Free-floating clot ends, as visualized on ultrasound, are at the highest risk for embolization. However, calf vein DVTs are thought to embolize occasionally, although it is difficult to prove that calf DVTs may not progress to the proximal system prior to embolization. Superficial venous thrombi must progress to the deep system prior to embolizing.40
As a thrombus ages, it also hardens. This organization results from a change in the makeup of a thrombus from mostly platelets to predominantly crosslinked fibrin.41 Hence, as the thrombus ages, it becomes less likely to embolize to the lungs.41 The probability of embolization decreases about 5-10 days after formation, due to the polymerization of fibrin strands.
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