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Deep Venous Thrombosis
Updated: Jan 16, 2009
Introduction
Introduction of acute deep venous thrombosis
Deep venous thrombosis (DVT) most commonly involves the deep veins of the leg or arm, often resulting in potentially life-threatening emboli to the lungs or debilitating venous alular dysfunction and chronic leg swelling. Deep venous thrombosis (DVT) is also one of the most prevalent medical problems today, with an annual incidence of 117 cases per 100,000. Each year in the United States, more than 200,000 people develop venous thrombosis; of those, 50,000 cases are complicated by pulmonary embolism.1 Early recognition and appropriate treatment of deep venous thrombosis (DVT) and its complications can save many lives.
Pathophysiology
Over a century ago, Rudolf Virchow described 3 factors that are critically important in the development of venous thrombosis: (1) venous stasis, (2) activation of blood coagulation, and (3) vein damage. Over time, refinements have been made in their description and importance to the development of venous thrombosis. The origin of venous thrombosis is frequently multifactorial, with components of the triad of variable importance in individual patients.
Studies have shown that low flow sites, such as the soleal sinuses, behind venous valve pockets, and at venous confluences, are at most risk for the development of venous thrombi.2,3 However, stasis alone is not enough to facilitate the development of venous thrombosis. Experimental ligation of rabbit jugular veins for periods of up to 60 minutes have failed to consistently cause venous thrombosis.4,5 Although, patients that are immobilized for long periods of time seem to be at high risk for the development of venous thrombosis, an additional stimulus is required to develop deep venous thrombosis (DVTs).
Mechanical injury to the vein wall appears to provide an added stimulus for venous thrombosis. Hip arthroplasty patients with the associated femoral vein manipulation represent a high-risk group that cannot be explained by just immobilization, with 57% of thrombi originating in the affected femoral vein rather than the usual site of stasis in the calf.6 Endothelial injury can convert the normally antithrombogenic endothelium to become prothrombotic by stimulating the production of tissue factor, von Willebrand factor, and fibronectin.
Genetic mutations within the blood’s coagulation cascade represent those at highest risk for the development of venous thrombosis (See Table 1). Primary deficiencies of coagulation inhibitors antithrombin, protein C, and protein S are associated with 5-10% of all thrombotic events.7 Resistance of procoagulant factors to an intact anticoagulation system has also recently been described with the recognition of factor V Leiden mutation, representing 10-65% of patients with deep venous thrombosis (DVT).8 In the setting of venous stasis, these factors are allowed to accumulate in thrombosis prone sites, where mechanical vessel injury has occurred, stimulating the endothelium to become prothrombotic.9
Components of the Virchow triad are of variable importance in individual patients, but the end result is early thrombus interaction with the endothelium. This interaction stimulates local cytokine production and facilitates leukocyte adhesion to the endothelium, both of which promote venous thrombosis. Depending on the relative balance between activated coagulation and thrombolysis, thrombus propagation occurs.
Over time, thrombus organization begins with the infiltration of inflammatory cells into the clot. This results in a fibroelastic intimal thickening at the site of thrombus attachment in most patients and a fibrous synechiae in up to 11%.10 In many patients, this interaction between vessel wall and thrombus leads to alular dysfunction and overall vein wall fibrosis. Histological examination of vein wall remodeling after venous thrombosis has demonstrated an imbalance in connective tissue matrix regulation and a loss of regulatory venous contractility that contributes to the development of chronic venous insufficiency.11,12
Risk factors
Many factors have been identified as known risk factors for the development of venous thrombosis. The single most powerful risk marker remains a prior history of DVT with up to 25% of acute venous thrombosis occurring in such patients.13 Pathologically, remnants of previous thrombi are often seen within the specimens of new acute thrombi. However, recurrent thrombosis may actually be the result of primary hypercoagulable states. Abnormalities within the coagulation cascade are the direct result of discrete genetic mutations within the coagulation cascade. Deficiencies of protein C, protein S, or antithrombin III account for approximately 5-10% of all cases of deep venous thrombosis (DVT).14
Age has been well studied as an independent risk factor for venous thrombosis development. Although a 30-fold increase in incidence is noted from age 30 to age 80, the effect appears to be multifactorial, with more thrombogenic risk factors occurring in the elderly than in those younger than 40 years.13,15 Venous stasis, as seen in immobilized patients and paralyzed limbs, also contributes to the development of venous thrombosis. Autopsy studies parallel the duration of bed rest to the incidence of venous thrombosis, with 15% of patients in those studies dying within 7 days of bedrest to greater than 80% in those dying after 12 weeks.2 Within stroke patients, deep venous thrombosis (DVT) is found in 53% of paralyzed limbs, compared with only 7% on the nonaffected side.16
Malignancy is noted in up to 30% of patients with venous thrombosis.13,17 The thrombogenic mechanisms involve abnormal coagulation, as evidenced by 90% of cancer patients having some abnormal coagulation factors.18 Chemotherapy may increase the risk of venous thrombosis by affecting the vascular endothelium, coagulation cascades, and tumor cell lysis. The incidence has been shown to increase in those patients undergoing longer courses of therapy for breast cancer, from 4.9% for 12 weeks of treatment to 8.8% for 36 weeks.19 Additionally, deep venous thrombosis (DVT) complicates 29% of surgical procedures done for malignancy.20
Postoperative venous thrombosis varies depending on a multitude of patient factors, including the type of surgery undertaken. Without prophylaxis, general surgery operations typically have an incidence of deep venous thrombosis (DVT) around 20%, while orthopedic hip surgery can occur in up to 50% of patients.21 Based on radioactive labeled fibrinogen, about half of lower extremity thrombi develop intraoperatively.22 Perioperative immobilization, coagulation abnormalities, and venous injury all contribute to the development of surgical venous thrombosis.
Other clinical settings commonly reported as risk factors have also been identified and are shown in Table 2 in Outcome and Prognosis.
Presentation
Clinical and diagnostic evaluation
The clinical diagnosis of deep venous thrombosis (DVT) is difficult and fraught with uncertainty. The classic signs and symptoms of deep venous thrombosis (DVT) are those associated with obstruction to venous drainage and include pain, tenderness, and unilateral leg swelling. Other associated nonspecific findings are warmth, erythema, a palpable cord, and pain upon passive dorsiflexion of the foot (Homan sign). However, even with patients with classic symptoms, up to 46% have negative venograms.23 Furthermore, up to 50% of those with image-documented venous thrombosis lack any specific symptom.24,25 Deep venous thrombosis (DVT) simply cannot be diagnosed or excluded based on clinical findings; thus, diagnostic tests must be performed whenever the diagnosis of deep venous thrombosis (DVT) is being considered.
When a patient has deep venous thrombosis (DVT), symptoms may be present or absent, unilateral or bilateral, or mild or severe. Thrombus that does not cause a net venous outflow obstruction is often asymptomatic. Thrombus that involves the iliac bifurcation, the pelvic veins, or the vena cava produces leg edema that is usually bilateral rather than unilateral. High partial obstruction often produces mild bilateral edema that is mistaken for the dependent edema of right-sided heart failure, fluid overload, or hepatic or renal insufficiency.
Severe venous congestion produces a clinical appearance that can be indistinguishable from the appearance of cellulitis. Patients with a warm, swollen, tender leg should be evaluated for both cellulitis and deep venous thrombosis (DVT) because patients with primary deep venous thrombosis (DVT) often develop a secondary cellulitis, while patients with primary cellulitis often develop a secondary deep venous thrombosis (DVT). Superficial thrombophlebitis, likewise, is often associated with a clinically inapparent underlying DVT.
If a patient is thought to have pulmonary embolism (PE) or has documented PE, the absence of tenderness, erythema, edema, or a palpable cord upon examination of the lower extremities does not rule out thrombophlebitis, nor does it imply a source other than a leg vein. More than two thirds of patients with proven PE lack any clinically evident phlebitis. Nearly one third of patients with proven PE have no identifiable source of deep venous thrombosis (DVT), despite a thorough investigation. Autopsy studies suggest that even when the source is clinically inapparent, it lies undetected within the deep venous system of the lower extremity and pelvis in 90% of cases.
The criterion standard to diagnostic imaging for deep venous thrombosis (DVT) remains venography with pedal vein cannulation, intravenous contrast injection, and serial limb radiographs. Identification of venous filling defects is diagnostic for venous thrombosis. However, the invasive nature and significant consumption of resources are only 2 of its many limitations.
Venous duplex ultrasound has now replaced venography as the diagnostic study of choice. Its noninvasive nature, wide availability, and minimal complications are only part of its popularity. A sensitivity and specificity of 97% and 94% on metaanalysis compared with venography have made duplex ultrasound the imaging of choice for venous thrombosis.26 Assessment of venous flow, vein compressibility, and identification of luminal echoes are all used in the making the diagnosis. However, duplex is limited by operator experience and body habitus. Other less-used imaging modalities include CT and MRI, but cost and the need to use intravenous contrast limit its use to specific clinical indications such as in the diagnosis of May-Thurner syndrome or thoracic outlet syndrome.
Laboratory analysis has also been used in aiding the diagnosis of venous thrombosis. D-dimers are degradation products of cross-linked fibrin by plasmin that are detected by diagnostic assays. Although highly sensitive, up to 97%, elevated levels are not specific with rates as low as 35%.27 Many other clinical situations can result in elevated D-dimer levels, including infection, trauma, postoperative states, and malignancy.28 Additional blood work should include coagulation studies to evaluate for a hypercoagulable state, if clinically indicated. A prolonged prothrombin time or activated partial thromboplastin time does not imply a lower risk of new thrombosis. Progression of deep venous thrombosis (DVT) and PE can occur despite full therapeutic anticoagulation in 13% of patients.
Prevention
Prevention of deep venous thrombosis (DVT) has long been studied in a variety of clinical situations with varying degrees of success. Primary prophylaxis is directed toward acting on one or more components of the Virchow triad, affecting blood flow, coagulation, or vessel wall endothelium. Studies have also addressed the timing for the initiation of prophylaxis and the duration.
Surgical patients undergoing general anesthesia have been extensively studies as described earlier with fatal PE rates ranging from 0.1-0.8% for all patients29,30 and up to 7% of patients undergoing surgery for fractured hips.31 Many different forms of therapy have been evaluated in this group. Intermittent pneumatic leg compression devices work by effectively increasing venous blood flow and activating the fibrinolytic system. Studies in cardiac surgery and neurosurgical patients have shown a distinct improvement in the incidence of deep venous thrombosis (DVT) without the added risk of bleeding.32,33 However, the effect is less impressive in higher-risk patients, and compliance can be difficult.
Anticoagulants represent another form of primary prophylaxis against venous thrombosis that has been extensively studies in recent years. The effectiveness of heparin has been established by numerous randomized clinical trials. Subcutaneous heparin of 5000 units given twice daily has been shown to not only decrease the incidence of deep venous thromboses (DVTs) but also prevents fatal PE. In one multicenter international trial, fatal PE was decreased from 0.7% to 0.1%.34
Vitamin K antagonists such as warfarin have also been shown to be an effective form of primary prophylaxis in high-risk patients. Therapy is often initiated the night prior to surgery; however, the anticoagulation effects of warfarin do not begin until the third day of use, preventing the propagation of clinically important thrombosis with less postoperative bleeding complications. Low-molecular weight heparin (LMWH) has been shown to be superior to both heparin and warfarin in high-risk patients such as those suffering from multitrauma and postorthopedic surgery.35 Equivalent results were seen in general surgery patients and medical patients.36,37
Timing and duration of prophylactic agents has also been determined to have a significant effect the development of deep venous thrombosis. Early prophylaxis in surgical patients with LMWH has been associated with significant reductions in postoperative venous thrombosis. Studies have shown that initiation of therapy within 8 hours of surgery has the greatest effect and is currently recommended by the American College of Chest Physicians.38 Additional recommendations by the ACCP for extended out-of-hospital prophylaxis have been made based on multiple randomized studies that have demonstrated an additional 7-10 days of anticoagulation decrease venous thrombosis rates without major bleeding issues.
Medical treatment
The mainstay of medical therapy has been anticoagulation since the introduction of heparin in the 1930s. Other anticoagulation drugs have subsequently been added to the treatment armamentarium over the years, such as vitamin K antagonists and low-molecular weight heparin. More recently, mechanical thrombolysis has become increasingly used as endovascular therapies have increased. Absolute contraindications to anticoagulation treatment include intracranial bleeding, severe active bleeding, recent brain, eye, or spinal cord surgery, and malignant hypertension. Relative contraindications include recent major surgery, recent cerebrovascular accident, and severe thrombocytopenia.
Initial anticoagulation therapy traditionally involves continuous intravenous heparin until adequate systemic anticoagulation is achieved. Rapid anticoagulation is essential within the first 24 hours of diagnosis, reducing the incidence of recurrent venous thrombosis during the first 3 months from 25% to 5%.39,40 Continuous intravenous heparin for therapy initiation has been increasingly replaced by single or twice daily subcutaneous injections of low-molecular weight heparin (LMWH). LMWH antithrombotic effects correlates with body weight and permit fixed dosing without laboratory monitoring that have been shown to be just as effective; it also allows for outpatient treatment of uncomplicated DVT.41,42 However, intravenous heparin remains the treatment of choice for those with endstage renal failure.
Long-term anticoagulation is necessary to prevent the high frequency of recurrent venous thrombosis or thromboembolic events. Interruption of anticoagulation within the first 12 weeks of therapy resulted in a 25% incidence of recurrent thrombosis.41 Oral vitamin K antagonists (warfarin) remain the preferred approach for long-term treatment, which allows for single dosing oral therapy that can be continued on an outpatient basis.
Warfarin interrupts the production of Vitamin K–dependent coagulation factor production by the liver. The effect is delayed by 72 hours until the existing circulating coagulation factors are cleared or used. The initial effect creates a hypercoagulable state because vitamin K–dependent anticoagulants (protein C and S) are cleared first from the body while vitamin K– dependent procoagulants continue to circulate. During this period, heparin anticoagulation is important to prevent worsening thrombosis. INR maintenance between 2.0 to 3.0 is recommended with higher ratios not improving effectiveness and lower ratios not reducing bleeding complications.43
The duration of therapy with warfarin has been evaluated by multiple prospective randomized clinical trials.41,44,45 Duration of therapy varies depending upon patient risk factors and presumed etiology. First-episode venous thrombosis or thrombotic event due to a transient reversible risk factor should be treated for at least 3 months. Interruption of therapy prior to 12 weeks results in an 8% absolute increase in recurrent thrombosis within the following 12 moths. Treatment for the entire 3 months results in an annual recurrent DVT incidence of 3%.
For patients with first episode idiopathic venous thrombosis, treatment length should be 6-12 months.41 However, the benefit of anticoagulation is lost after stopping treatment at one year, prompting many physicians to continue treatment indefinitely.46 The decision to continue anticoagulation should be tailored to each patient, taking into consideration bleeding risk and patient preference with treatment reassessment at periodic intervals.
For patients with a first-episode venous thrombosis and a documented antiphospholipid antibodies or 2 or more thrombophilic conditions (combined factor V Leiden and prothrombin 20210A gene mutations), at least 12 months of treatment is indicated. Six to 12 months of initial therapy is indicated in those patients with any one of the following: deficiencies of antithrombin, protein C, or protein S; factor V Leiden; prothrombin 20210A; hyperhomocysteinemia; or high factor VIII levels (>90th percentile). Indefinite therapy is also considered in both of these patient populations.41
Indefinite therapy is recommended for patients with recurrent episodes of venous thrombosis regardless of the cause. The risk of recurrent thromboembolism during a 4-year follow-up period was reduced from 21% to 3% with continued anticoagulation. However, the incidence of major bleeding increased from 3% to 9%.45
Long-term therapy with LMWH has been shown to be as effective as warfarin in the treatment of venous thrombosis, except in those patients with a concurrent malignancy. In this subgroup, LMWH was shown to be more effective than oral therapy.47,48 Initial studies have also shown LMWH to be effective in pregnant patients, but long-term, large randomized trials have yet to be completed.49
The main adverse effects of heparin therapy include bleeding and thrombocytopenia. Approximately 2% of patients experience major bleeding within the first 3 months of therapy and 1-3% thereafter per year.50 The estimated fatality rate for each episode of major bleeding is 13%.50 The development of thrombocytopenia must alert clinicians to the diagnosis of heparin-induced thrombocytopenia (HIT), which can occur in up to 3% of patients treated with heparin for greater than 4 days. Two types exist; the most common form is a self-limiting nonimmune mediated thrombocytopenia that resolves with cessation of therapy. The less common immune-mediated thrombocytopenia has potentially catastrophic thromboembolic complications.
Consensus statements from the American College of Chest Physicians regarding antithrombitic therapy for venous thromboembolic disease are referenced in the Further Reading section.
Relevant Anatomy
The peripheral venous system functions both as a reservoir to hold extra blood and as a conduit to return blood from the periphery to the heart and lungs. Unlike arteries, which possess 3 well-defined layers (a thin intima, a well-developed muscular media, and a fibrous adventitia), most veins are composed of a single tissue layer. Only the largest veins possess internal elastic membranes, and this layer is thin and unevenly distributed, providing little buttress against high internal pressures. The correct functioning of the venous system depends on a complex series of valves and pumps that are individually frail and prone to malfunction, yet the system as a whole performs remarkably well under extremely adverse conditions.
Primary collecting veins of the lower extremity are passive, thin-walled reservoirs that are tremendously distensible. Most are suprafascial, surrounded by loosely bound alveolar and fatty tissue that is easily displaced. These suprafascial collecting veins can dilate to accommodate large volumes of blood with little increase in back pressure so that the volume of blood sequestered within the venous system at any moment can vary by a factor of 2 or more without interfering with the normal function of the veins. Suprafascial collecting veins belong to the superficial venous system.
Outflow from collecting veins is via secondary conduit veins that have thicker walls and are less distensible. Most of these veins are subfascial and are surrounded by tissues that are dense and tightly bound. These subfascial veins belong to the deep venous system, through which all venous blood must eventually pass through on its way back to the right atrium of the heart. The lower limb deep venous system is typically thought of as 2 separate systems, one below the knee and one above.
The calf has 3 groups of paired deep veins: the anterior tibial veins, draining the dorsum of the foot; the posterior tibial veins, draining the sole of the foot; and the peroneal veins, draining the lateral aspect of the foot. Venous sinusoids within the calf muscle coalesce to form soleal and gastrocnemius intramuscular venous plexuses, which join the peroneal veins in the mid calf. These veins play an important role in the muscle pump function of the calf. Just below the knee, these tibial veins join to become the popliteal vein, which too can be paired on occasion.
Together, the calf’s muscles and deep vein system form a complex array of valves and pumps, often referred to as the “peripheral heart,” that functions to push blood upward from the feet against gravity. The calf-muscle pump is analogous to the common hand-pump bulb of a sphygmomanometer filling a blood pressure cuff. Before pumping has started, the pressure is neutral and equal everywhere throughout the system and the calf fills with blood, typically 100-150 mL. When the calf contracts, the feeding perforator vein valves are forced closed and the outflow valves are forced open driving the blood proximally. When the calf is allowed to relax, the veins and sinusoids refill from the superficial venous system via perforating veins, and the outflow valve is then forced shut, preventing retrograde flow. With each “contraction,” 40-60% of the calf’s venous volume is driven proximally.51
The deep veins of the thigh begin distally with the popliteal vein as it courses proximally behind the knee and then passes through the adductor canal, at which point its name changes to the femoral vein. This important deep vein is sometimes incorrectly referred to as the superficial femoral vein in a misguided attempt to distinguish it from the profunda femora, or deep femoral vein, a short, stubby vein that usually has its origin in terminal muscle tributaries within the deep muscles of the lateral thigh but may communicate with the popliteal vein in up to 10% of patients. In the proximal thigh, the femoral vein and the deep femoral vein unite to form the common femoral vein, which passes upwards above the groin crease to become the iliac vein.
The misleading and incorrect term superficial femoral vein should never be used because the femoral vein is a deep vein and is not part of the superficial venous system. The incorrect term does not appear in any definitive anatomic atlas, yet it has come into common use in vascular laboratory practice. Confusion arising from use of the inappropriate name has been responsible for many cases of clinical mismanagement and death.
The external iliac vein is the continuation of the femoral vein as it passes upward behind the inguinal ligament. At the level of the sacroiliac joint, it unites with the hypogastric vein to form the common iliac vein. The left common iliac is longer than the right and more oblique in its course, passing behind the right common iliac artery. This anatomic asymmetry sometimes results in compression of the left common iliac vein by the right common iliac artery to produce May-Thurner syndrome, a left-sided iliac outflow obstruction with localized adventitial fibrosis and intimal proliferation, often with associated DVT. At the level of the fifth lumbar vertebra, the 2 common iliac veins come together at an acute angle to form the inferior vena cava.
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Further Reading
- Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S-545S.
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):381S-453S.
Keywords
deep vein thrombosis, thromboembolism, blood clots, phlebitis, venous claudication, DVT, venous thromboembolic disease, VTE disease, venous thromboembolism, VTE, pulmonary thromboembolism, PTE, pulmonary embolism, PE, blood clot, thrombus formation, venous thrombosis, deep vein thrombus, deep vein thrombi, deep venous thrombus, deep venous thrombi, obstructed venous outflow, chronic venous insufficiency, CVI, postphlebitic syndrome
