Despite increased awareness and use of prophylactic modalities, DVT and pulmonary embolism (PE), or VTE, remain important preventable sources of morbidity and mortality, especially in the surgical patient. The incidence of VTE is approximately 100 per 100,000 people per year in the general population, with 20% of the diagnoses made within 3 months of a surgical procedure. Of the symptomatic patients, one third will present with PE and two thirds with DVT.5,6 The estimated number of cases of VTE may well be over 600,000 per year in the United States, making it a major U.S. health problem.7 Furthermore, death occurs in 6% of DVT and 12% of PE cases within 1 month of diagnosis.5 Not only does VTE pose a veritable threat to life, but it also places patients at higher risk for recurrence and post-VTE sequelae such as pulmonary hypertension and postthrombotic syndrome, with 4% and up to 30% incidence, respectively.8,9,10
Three conditions, first described by Rudolf Virchow in 1862, contribute to VTE formation: stasis of blood flow, endothelial damage, and hypercoagulability. Of these risk factors, relative hypercoagulability appears most important in most cases of spontaneous VTE, or so-called idiopathic VTE, whereas stasis and endothelial damage likely play a greater role in secondary VTE, or so-called provoked VTE, occurring in association with transient risk factors such as immobilization, surgical procedures, and trauma. Identifiable risk factors for VTE generally relate to one of the conditions described by Virchow. Often more than one risk factor is present. Specific risk factors for VTE are listed in Table 24-2.
Table 24-2Risk factors for venous thromboembolism ||Download (.pdf) Table 24-2 Risk factors for venous thromboembolism
Hormone replacement therapy and oral contraceptive use
Pregnancy and puerperium
Prior venous thromboembolism
Trauma or spinal cord injury
Long-haul travel (>6 hours)
Antiphospholipid antibody syndrome
Factor V Leiden
Protein C deficiency
Protein S deficiency
Factor XI elevation
Factor VII, VIII, IX, XI elevation
Activated protein C resistance without factor V Leiden
The more common acquired VTE risk factors include older age (>40 years), hospitalization and immobilization, hormone replacement and oral contraceptive therapy, pregnancy and the recently postpartum state, prior VTE, malignancy, major surgery, obesity, nephrotic syndrome, trauma and spinal cord injury, long-haul travel (>6 hours), varicose veins, antiphospholipid syndrome, myeloproliferative disorders, and polycythemia. Heritable risk factors include male sex, factor V Leiden mutation; prothrombin 20210A gene variant; antithrombin, protein C, and protein S deficiencies; and dysfibrinogenemias. In some patients, the cause of the thrombophilia may have both a heritable and an acquired component. These mixed causes include homocysteinemia; factor VII, VIII, IX, and XI elevation; hyperfibrinogenemia; and activated protein C resistance in the absence of factor V Leiden.11 There may be a synergistic effect when particular multiple inherited and acquired risk factors are present in the same patient.
Other patient-specific factors associated with venous thrombosis include the traditional cardiovascular risk factors of obesity, hypertension, and diabetes. VTE is more common in whites and African Americans than Asians and Native Americans.12,13 Certain gene variants (single nucleotide polymorphisms) are also associated with a mildly increased risk for VTE, and their presence may interact with other risk factors to increase the overall risk for venous thrombosis.14
Anatomic factors may also contribute to development of DVT. At the site where the right iliac artery crosses over the left iliac vein, the left iliac vein may become chronically narrowed predisposing to iliofemoral venous thrombosis, so-called May-Thurner syndrome. External compression of major veins by masses of various types can also lead to venous thrombosis.
Many cases of VTE are potentially preventable. Accordingly, in current clinical practice, preoperative VTE risk assessment is becoming increasingly common to identify patients at moderate and high risk. Scoring systems have been developed that take into account the number of VTE risk factors in an individual patient. These risk stratification scores, such as the Rogers score15 and Caprini score,16 provide individual patient risk stratification and recommendations for prophylactic anticoagulation. The ninth edition of the American College of Chest Physicians (ACCP) Guidelines for Prevention of VTE in Non-Orthopedic Surgical Patients acknowledges both the Rogers and Caprini scores and provides recommendations for VTE prophylaxis (Table 24-3). Orthopedic surgical patients are generally excluded from risk assessment scores because of the disproportionately increased risk of VTE in orthopedic surgery compared with the general and abdominopelvic surgery population.
Table 24-3Thromboembolism risk and recommended thromboprophylaxis in surgical patients ||Download (.pdf) Table 24-3 Thromboembolism risk and recommended thromboprophylaxis in surgical patients
|LEVEL OF RISK ||APPROXIMATE DVT RISK WITHOUT THROMBOPROPHYLAXIS (%) ||SUGGESTED THROMBOPROPHYLAXIS OPTIONS |
Very low risk
General or abdominopelvic surgery
|<0.5% (Rogers score <7; Caprini score 0) || |
No specific thromboprophylaxis
General or abdominopelvic surgery
|~1.5% (Rogers score 7–10; Caprini score 1–2) ||Mechanical prophylaxis |
General or abdominopelvic surgery
|~3.0% (Rogers score >10; Caprini score 3–4) ||LMWH (at recommended doses), LDUH, or mechanical prophylaxis |
|High bleeding risk || ||Mechanical prophylaxis |
General or abdominopelvic surgery
|~6% (Caprini score ≥5) ||LMWH (at recommended doses), fondaparinux and mechanical prophylaxis |
High bleeding risk
General or abdominopelvic surgery for cancer
| || |
Extended-duration LMWH (4 weeks)
Early in the course of DVT development, venous thrombosis is thought to begin in an area of relative stasis, such as a soleal sinus vein or immediately downstream of the cusps of a venous valve in the axial calf veins. Isolated proximal DVT without tibial vein thrombosis is unusual. Early in the course of a DVT, there may be no or few clinical findings such as pain or swelling. Even extensive DVT may sometimes be present without signs or symptoms. History and physical examination are therefore unreliable in the diagnosis of DVT. In addition, symptoms and signs generally associated with DVT, such as extremity pain and/or swelling, are nonspecific. In large studies, DVT has been found by venography or DUS in ≤50% of patients in whom it was clinically suspected.17,18 Objective studies are therefore required to confirm a diagnosis of VTE or to exclude the presence of VTE.
Clinical symptoms may worsen as DVT propagates and involves the major proximal deep veins. Extensive DVT of the major axial deep venous channels of the lower extremity with relative sparing of collateral veins causes a condition called phlegmasia cerulea dolens (Fig. 24-4). This condition is characterized by pain and pitting edema with associated cyanosis. When the thrombosis extends to the collateral veins, massive fluid sequestration and more significant edema ensue, resulting in a condition known as phlegmasia alba dolens.19 The affected extremity in phlegmasia alba dolens is extremely painful and edematous and pale secondary to arterial insufficiency from dramatically elevated below lower knee compartment pressures. Both phlegmasia cerulean dolens and phlegmasia alba dolens can be complicated by venous gangrene and the need for amputation.
Phlegmasia cerulea dolens of the left leg. Note the bluish discoloration.
Vascular Lab and Radiologic Evaluation
DUS is now the most commonly performed test for the detection of infrainguinal DVT, both above and below the knee, and has a sensitivity and specificity of >95% in symptomatic patients.3 DUS refers to the combination of real-time B-mode ultrasound with pulsed Doppler capability. For VTE detection, color flow imaging is an extremely useful adjunct in the evaluation of possible calf vein DVT and evaluation of intra-abdominal veins. DUS provides the ability to noninvasively visualize venous anatomy, detect occluded and partially occluded venous segments, and demonstrate physiologic flow characteristics using a mobile self-contained device.
In the supine patient, normal lower extremity venous flow is phasic (Fig. 24-5), decreasing with inspiration in response to increased intra-abdominal pressure with the descent of the diaphragm and then increasing with expiration as the diaphragm rises and intra-abdominal pressure decreases. When the patient is upright, the decrease in intra-abdominal pressure with expiration cannot overcome the hydrostatic column of pressure existing between the right atrium and the calf. Muscular contractions of the calf, along with the one-way venous valves, are then required to promote venous return to the heart. Flow also can be increased by leg elevation or compression and decreased by sudden elevation of intra-abdominal pressure (Valsalva maneuver). In a venous DUS examination performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to Valsalva maneuver are all assessed. From the common femoral through the popliteal vein, the primary method of detecting DVT with ultrasound is demonstration of the lack of compressibility of the vein with probe pressure on B-mode imaging. Normally, in transverse section, the vein walls should coapt with pressure. Lack of coaptation indicates thrombus. Calf vein thrombi are often best detected by abnormalities in color flow imaging.
Duplex ultrasound scan of a normal femoral vein with phasic flow signals.
The examination begins at the ankle and continues proximally to the groin. Each vein is visualized, and the flow signal is assessed with distal and proximal compression. Lower extremity DVT can be diagnosed by any of the following DUS findings: lack of spontaneous flow (Fig. 24-6), inability to compress the vein (Fig. 24-7), absence of color filling of the lumen by color flow DUS, loss of respiratory flow variation, and venous distention. Again, lack of venous compression on B-mode imaging is the primary diagnostic variable. Several studies comparing B-mode ultrasound to venography for the detection of femoropopliteal DVT in patients clinically suspected to have DVT report sensitivities of >91% and specificities of >97%.20,21 The ability of DUS to assess isolated calf vein DVT varies greatly, with sensitivities ranging from 50% to 93% and specificities approaching 100%.22,23
Duplex ultrasound of a femoral vein containing thrombus demonstrating no flow within the femoral vein.
B-mode ultrasound of the femoral vein in cross-section. The femoral vein does not collapse with external compression (arrows).
Impedance plethysmography (IPG) was the primary noninvasive method of diagnosing DVT before the widespread use of DUS but is infrequently used today. Changes in electrical resistance resulting from lower extremity blood volume changes are quantified. IPG is less accurate than DUS for the detection of proximal DVT, with 83% sensitivity in symptomatic patients. It is a poor detector of calf vein DVT.24
Iodine-125 Fibrinogen Uptake
Iodine-125 fibrinogen uptake (FUT) is a seldom used technique that involves IV administration of radioactive fibrinogen and monitoring for increased uptake in fibrin clots. An increase of 20% or more in one area of a limb indicates an area of thrombus. FUT can detect DVT in the calf, but high background radiation from the pelvis and the urinary tract limits its ability to detect proximal DVT. It also cannot be used in an extremity that has recently undergone surgery or has active inflammation. In a prospective study, FUT had a sensitivity of 73% and specificity of 71% for identification of DVT in a group of symptomatic and asymptomatic patients.25 Currently, FUT is primarily a research tool of historic interest.
Venography is the gold standard to which other diagnostic modalities are compared. A small catheter is placed in a dorsal foot vein with injection of a radiopaque contrast agent. Radiographs are obtained in at least two projections. A positive study result is failure to fill the deep system with passage of the contrast medium into the superficial system or demonstration of discrete filling defects (Fig. 24-8). A normal study result virtually excludes the presence of DVT. In a study of 160 patients with a normal venogram followed for 3 months, only two patients (1.3%) subsequently developed DVT and no patients experienced symptoms of PE.26 Venography is not routinely used in clinical practice due to invasiveness and complication risk. It is still, however, frequently used in research studies evaluating DVT prophylaxis.
Venogram showing a filling defect in the popliteal vein (arrows).
Once the diagnosis of VTE has been made, antithrombotic therapy should be initiated promptly. If clinical suspicion for VTE is high, it may be prudent to start treatment while the diagnosis is objectively confirmed. The goals of VTE treatment are the prevention of mortality and morbidity associated with PE and the prevention of the postthrombotic syndrome (PTS). Treatment regimens may include antithrombotic therapy, temporary or permanent vena cava filter placement, catheter-directed or systemic thrombolytic therapy, and operative thrombectomy.
Most often, antithrombotic therapy for VTE is initiated with IV or subcutaneous (SC) unfractionated heparin or SC low molecular weight heparin. Fondaparinux, a synthetic pentasaccharide, is sometimes also used as an alternative to heparin to initiate therapy. An oral vitamin K antagonist, usually sodium warfarin, is begun shortly after initiation of IV or SC therapy. Either SC or IV therapy is continued until effective oral anticoagulation with warfarin is achieved as indicated by an international normalized ratio (INR) ≥2 for 24 hours. A minimum of 5 days of heparin or fondaparinux therapy is recommended.27 Recently, the U.S. Food and Drug Administration (FDA) has also approved alternative oral anticoagulants for both treatment and prophylaxis for VTE.
Unfractionated heparin (UFH) binds to antithrombin via a specific 18-saccharide sequence. This increases antithrombin activity over 1000-fold. The antithrombin-heparin complex primarily inhibits factor IIa (thrombin) and factor Xa and, to a lesser degree, factors IXa, XIa, and XIIa of the coagulation cascade. In addition, UFH also binds to tissue factor pathway inhibitor, which inhibits the conversion of factor X to Xa, and factor IX to IXa. Finally, UFH catalyzes the inhibition of thrombin by heparin cofactor II via a mechanism independent of antithrombin.
UFH therapy is most commonly administered with an initial IV bolus of 80 units/kg. Weight-based UFH dosages have been shown to be more effective than standard fixed boluses in rapidly achieving therapeutic levels.28 The initial bolus is followed by a continuous IV drip at 18 units/kg per hour. The half-life of IV UFH ranges from 45 to 90 minutes and is dose dependent. The level of antithrombotic therapy should be monitored every 6 hours using the activated partial thromboplastin time (aPTT), with the goal range of 1.5 to 2.5 times control values. This should correspond with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL.
Initial anticoagulation with UFH may also be administered SC, although this route is less commonly used. Adjusted-dose therapeutic SC UFH is initiated with 17,500 units, followed by 250 units/kg twice daily, and dosing is adjusted to an aPTT goal range similar to that for IV UFH. Fixed-dose unmonitored SC UFH is started with a bolus of 333 units/kg, followed by 250 units/kg twice daily.29
Hemorrhage is the primary complication of UFH therapy. The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of >2 units of packed red blood cells) is approximately 5% in hospitalized patients undergoing UFH therapy (1% in medical patients and 8% in surgical patients).29 For patients with UFH-related bleeding complications, cessation of UFH is required, and anticoagulation may be reversed with protamine sulfate. Protamine sulfate binds to UFH and forms an inactive salt compound. Each milligram of protamine neutralizes 90 to 115 units of heparin, and the dosage should not exceed 50 mg IV over any 10-minute period. Side effects of protamine sulfate include hypotension, pulmonary edema, and anaphylaxis. Patients with prior exposure to protamine-containing insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established. Protamine administration should be terminated if any side effects occur.
In addition to hemorrhage, heparin also has unique complications. Heparin-induced thrombocytopenia (HIT) results from heparin-associated antiplatelet antibodies (HAAbs) directed against platelet factor 4 complexed with heparin.30 HIT occurs in 1% to 5% of patients being treated with heparin.31,32 In patients with repeat heparin exposure (such as vascular surgery patients), the incidence of HAAbs may be as high as 21%.33 HIT occurs most frequently in the second week of therapy and may lead to disastrous venous or arterial thrombotic complications. Therefore, platelet counts should be monitored periodically in patients receiving continuous heparin therapy.
HIT is diagnosed based on previous exposure to heparin, platelet count less than 100,000, and/or platelet count decline of 50% following exposure. All heparin must be stopped and alternative anticoagulation initiated immediately to avoid thrombotic complications, which may approach 50% over the subsequent 30 days in affected individuals.34
Another complication of prolonged high-dose heparin therapy is osteopenia. Heparin-induced osteopenia results from impairment of bone formation and enhancement of bone resorption by heparin.
Low molecular weight heparins (LMWHs) are derived from the depolymerization of porcine UFH. Like UFH, LMWHs bind to antithrombin via a specific pentasaccharide sequence to expose an active site for the neutralization of factor Xa. However, LMWHs have fewer additional saccharide units. This results in less inactivation of thrombin (factor IIa). In comparison to UFH, LMWHs have increased bioavailability (>90% after SC injection), longer half-lives (approximately 4 to 6 hours), and more predictable elimination rates.
Most patients treated with weight-based once- or twice-daily SC LMWH injections do not require laboratory monitoring for anticoagulant effect, a distinct advantage over continuous IV infusions of UFH. Patients who do require monitoring include those with significant renal insufficiency, pediatric patients, obese patients greater than 120 kg, and pregnant patients. Monitoring may be performed using anti-Xa activity assays. The therapeutic anti-Xa goal range depends on the type of LMWH and the frequency of dosing. There are numerous LMWHs available, and the various preparations differ in their anti-Xa and anti-IIa activities. Treatment dosing for one LMWH therefore cannot be extrapolated for use with another. The anticoagulant effect of LMWHs may be partially reversed (approximately 60%) with protamine sulfate.
Numerous well-designed trials comparing SC LMWH with IV and SC UFH for the treatment of DVT have been critically evaluated in several meta-analyses and demonstrate a decrease in thrombotic complications, bleeding, and mortality with LMWHs.35,36,37 LMWHs also are associated with a decreased rate of HAAb formation and HIT (<2%) compared with UFH (at least in prophylactic doses).29 However, patients with established HIT also should not receive LMWHs because there is cross-reactivity between the drugs.38
A major benefit of LMWHs is that it allows outpatient treatment of VTE.39,40 In a randomized study comparing IV UFH and the LMWH nadroparin calcium,39 there was no significant difference in recurrent thromboembolism (8.6% for UFH vs. 6.9% for LMWH) or major bleeding complications (2.0% for UFH vs. 0.5% for LMWH). There was, however, a 67% reduction in mean days in the hospital for the LMWH group.
Fondaparinux currently is a synthetic pentasaccharide that has been approved by the FDA for the initial treatment of DVT and PE. Its five-polysaccharide sequence binds and activates antithrombin, causing specific inhibition of factor Xa. In two large noninferiority trials, fondaparinux was compared with the LMWH enoxaparin for the initial treatment of DVT and with IV UFH for the initial treatment of PE.41,42 The rates of recurrent VTE ranged from 3.8% to 5%, with rates of major bleeding of 2% to 2.6%, for all treatment arms. The drug is administered SC once daily with a weight-based dosing protocol: 5 mg, 7.5 mg,or 10 mg for patients weighing <50 kg, 50 to 100 kg, or >100 kg, respectively. The half-life of fondaparinux is approximately 17 hours in patients with normal renal function. There are rare case reports of fondaparinux-induced thrombocytopenia.43
Direct thrombin inhibitors (DTIs) include recombinant hirudin, argatroban, and bivalirudin. These antithrombotic agents bind to thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet activation. These actions are independent of antithrombin. The DTIs should be reserved for (a) patients in whom there is a high clinical suspicion or confirmation of HIT, and (b) patients who have a history of HIT or test positive for heparin-associated antibodies. In patients with established HIT, DTIs should be administered for at least 7 days, or until the platelet count normalizes. Warfarin may then be introduced slowly, overlapping therapy with a DTI for at least 5 days.44
Bivalirudin is approved primarily for patients with or without HIT who undergo percutaneous coronary intervention and is rarely used outside of that setting.
Commercially available hirudin is manufactured using recombinant DNA technology. It is indicated for the prophylaxis and treatment of patients with HIT. In patients with normal renal function, recombinant hirudin is administered as an IV bolus dose of 0.4 mg/kg, followed by a continuous IV infusion of 0.15 mg/kg per hour. The half-life ranges from 30 to 60 minutes. The aPTT is monitored, starting approximately 4 hours after initiation of therapy, and dosage is adjusted to maintain an aPTT of 1.5 to 2.5 times the laboratory normal value. The less commonly used ecarin clotting time is an alternative method of monitoring. Recombinant hirudin is eliminated via renal excretion, so dosage adjustments are required in patients with renal insufficiency.
Argatroban is indicated for the prophylaxis and treatment of thrombosis in HIT. It also is approved for patients with, or at risk for, HIT undergoing percutaneous coronary intervention. Antithrombotic prophylaxis and therapy are initiated with a continuous IV infusion of 2 μg/kg per minute, without the need for a bolus. The half-life ranges from 39 to 51 minutes, and the dosage is adjusted to maintain an aPTT of 1.5 to 3 times normal. Large initial boluses and higher rates of continuous infusion are reserved for patients with coronary artery thrombosis and myocardial infarction. In these patients, therapy is monitored using the activated clotting time. Argatroban is metabolized and excreted by the liver; therefore, dosage adjustments are needed in patients with hepatic impairment. There is no reversal agent for argatroban.
Vitamin K antagonists, which include warfarin and other coumarin derivatives, are the mainstay of long-term antithrombotic therapy in patients with VTE. Warfarin inhibits the γ-carboxylation of vitamin K–dependent procoagulants (factors II, VII, IX, and X) and anticoagulants (proteins C and S), resulting in formation of less functional proteins. Warfarin usually requires several days to achieve full effect because normal circulating coagulation proteins must first undergo their normal degradation. Factors X and II have the longest half-lives, in the range of 36 and 72 hours, respectively. A steady-state concentration of warfarin is usually not reached for 4 to 5 days.
Warfarin therapy is monitored by measuring the INR, calculated using the following equation:
INR = (patient prothrombin time/laboratory normal prothrombin time)ISI
where ISI is the international sensitivity index. The ISI describes the strength of the thromboplastin that is added to activate the extrinsic coagulation pathway. The therapeutic target INR range is usually 2.0 to 3.0, but the response to warfarin is variable and depends on liver function, diet, age, and concomitant medications. In patients receiving anticoagulation therapy without concomitant thrombolysis or venous thrombectomy, the vitamin K antagonist may be started on the same day as the initial parenteral anticoagulant, usually at doses ranging from 5 to 10 mg. Smaller initial doses may be needed in older and malnourished patients, in those with liver disease or congestive heart failure, and in those who have recently undergone major surgery.45
The recommended duration of warfarin antithrombotic therapy is stratified based on whether the DVT was provoked or unprovoked, whether it was the first or a recurrent episode, where the DVT is located, and whether malignancy or thrombophilia is present. Current ACCP recommendations for duration of warfarin therapy are summarized in Table 24-4.
Table 24-4Summary of American College of Chest Physicians recommendations regarding duration of long-term antithrombotic therapy for deep vein thrombosis (DVT) ||Download (.pdf) Table 24-4 Summary of American College of Chest Physicians recommendations regarding duration of long-term antithrombotic therapy for deep vein thrombosis (DVT)
|CLINICAL SUBGROUP ||ANTITHROMBOTIC TREATMENT DURATION |
|First episode DVT/transient risk/surgery ||VKA or LMWH for 3 months |
First episode DVT/unprovoked
VKA or LMWH for 3 months
Consider for long-term therapy if:
• Proximal DVT
• Minimal bleeding risk
• Stable coagulation monitoring
• Asymptomatic and no risk factors for progression
VKA for 3 months
Serial imaging in 2 weeks, if progression VKA for 3 months
Second episode DVT/ unprovoked
DVT and cancer
VKA for extended therapy
LMWH for extended therapy over VKA
In patients with proximal DVT, several randomized clinical trials have demonstrated that shorter-term antithrombotic therapy (4 to 6 weeks) is associated with a higher rate of VTE recurrence than 3 to 6 months of anticoagulation.46,47,48 In these trials, most of the patients with transient risk factors had a low rate of recurrent VTE, and most recurrences were in patients with continuing risk factors. The ACCP recommendation, therefore, is that 3 months of anticoagulation are sufficient to prevent recurrent VTE in patients with DVT occurring around the time of a transient risk factor (e.g., hospitalization, orthopedic or major general surgery).
In contrast to patients with thrombosis related to transient risk factors, patients with idiopathic VTE are much more likely to develop recurrence (rates as high as 40% at 10 years). In this latter group of patients, numerous clinical trials have compared 3 to 6 months of anticoagulation therapy with extended-duration warfarin therapy, both at low intensity (INR of 1.5 to 2.0) and at conventional intensity (INR of 2.0 to 3.0).49,50,51 In patients with idiopathic DVT, extended-duration antithrombotic therapy is associated with a relative reduction in the rate of recurrent VTE by 75% to >90%. In addition, conventional-intensity warfarin reduces the risk even further compared with low-intensity warfarin (0.7 events per 100 person-years vs. 1.9 events per 100 person-years) without an increase in bleeding complications.52
In patients with VTE in association with a hypercoagulable condition, the optimal duration of anticoagulation therapy is influenced more by the clinical circumstances at the time of the VTE (idiopathic vs. secondary) than by the actual presence or absence of the more common thrombophilic conditions. In patients with VTE related to malignancy, increasing evidence suggests that longer-term therapy with LMWH (up to 6 months) is associated with a lower VTE recurrence than treatment using conventional vitamin K antagonists.53,54 The primary complication of warfarin therapy is hemorrhage, and the risk is related to the magnitude of INR prolongation. Depending on the INR and the presence of bleeding, warfarin anticoagulation may be reversed by (a) omitting or decreasing subsequent dosages, (b) administering oral or parenteral vitamin K, or (c) administering fresh-frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa.45
Warfarin therapy rarely may be associated with the development of skin necrosis and limb gangrene. These conditions occur more commonly in women (4:1), and the most commonly affected areas are the breast, buttocks, and thighs. This complication, which usually occurs in the first days of therapy, is occasionally, but not exclusively, associated with protein C or S deficiency and malignancy. Patients who require continued anticoagulation may restart low-dose warfarin (2 mg) while receiving concomitant therapeutic heparin. The warfarin dosage is then gradually increased over a 1- to 2-week period.45
Systemic and Catheter-Directed Thrombolysis
Patients with extensive proximal, iliofemoral DVT may benefit from systemic thrombolysis or catheter-directed thrombolysis (CDT). CDT appears to be more effective (see later in chapter) and potentially reduces acute congestive lower extremity symptoms more rapidly than anticoagulation alone and decreases the development of PTS.
Several thrombolytic agents are available, including streptokinase, urokinase, alteplase (recombinant tissue plasminogen activator), reteplase, and tenecteplase. All share the ability to convert plasminogen to plasmin, which leads to the degradation of fibrin. They differ with regard to their half-lives, their potential for inducing fibrinogenolysis (generalized lytic state), their potential for antigenicity, and their FDA-approved indications for use.
Streptokinase is purified from β-hemolytic Streptococcus and is approved for the treatment of acute myocardial infarction, PE, DVT, arterial thromboembolism, and occluded central lines and arteriovenous shunts. It is not specific for fibrin-bound plasminogen, however, and its use is limited by its significant rates of antigenicity. Fevers and shivering occur in 1% to 4% of patients.
Urokinase is derived from human neonatal kidney cells grown in tissue culture. Currently, it is only approved for lysis of massive PE or PE associated with unstable hemodynamics.
Alteplase, reteplase, and tenecteplase all are recombinant variants of tissue plasminogen activator. Alteplase is indicated for the treatment of acute myocardial infarction, acute ischemic stroke, and acute massive PE. However, it often is used for CDT of DVT. Reteplase and tenecteplase are indicated only for the treatment of acute myocardial infarction.
Systemic thrombolysis was evaluated in numerous older prospective and randomized clinical trials, and its efficacy was summarized in a recent Cochrane Review.55 In 12 studies involving over 700 patients, systemic thrombolysis was associated with significantly more clot lysis (relative risk [RR] 0.24 to 0.37) and significantly less PTS (RR 0.66). However, venous function was not significantly improved. In addition, more bleeding complications occurred (RR 1.73).
In an effort to minimize bleeding complications and increase efficacy, CDT techniques were developed for the treatment of symptomatic primarily iliofemoral DVT. With catheter-directed therapy, venous access may be achieved through percutaneous catheterization of the ipsilateral popliteal vein, retrograde catheterization through the contralateral femoral vein, or retrograde cannulation from the internal jugular vein. Multi-side-hole infusion catheters, with or without infusion wires, are used to deliver the lytic agent directly into the thrombus. Lytic agents may be administered alone or, now more commonly, in combination with catheter-based methods to physically break up the clot—so-called pharmacomechanical thrombolysis.
The efficacy of CDT for the treatment of symptomatic iliofemoral DVT has been reported in a large multicenter randomized control trial. Two-hundred and nine patients with proximal DVT were assigned to conventional anticoagulant therapy versus conventional anticoagulant therapy plus CDT. In the CDT group, placement of a venous stent was permitted for any identified iliac vein stenotic lesion. At 6 months, iliac vein patency was significantly improved in the thrombolysis group (65.9% vs. 47.4%). At 2 years, in the CDT group, there was an absolute risk reduction of nearly 15% for development of PTS, translating to a number needed to treat of seven patients to prevent one case of PTS.56
Inferior Vena Caval Filters
Since the introduction of the Kimray-Greenfield filter in the United States in 1973, numerous vena caval filters have been developed. Although the designs are variable, they all prevent pulmonary emboli, while allowing continuation of venous blood flow through the IVC. Early filters were placed surgically through the femoral vein. Currently, less invasive techniques allow percutaneous filter placement through a femoral vein, internal jugular vein, or small peripheral vein under fluoroscopic or ultrasound guidance.
Placement of an IVC filter is indicated for patients who have manifestations of lower extremity VTE and absolute contraindications to anticoagulation, those that have a bleeding complication from anticoagulation therapy of acute VTE, or those who develop recurrent DVT or PE despite adequate anticoagulation therapy and for patients with severe pulmonary hypertension.
When possible, therapy should be continued in patients with vena cava filters. The duration of anticoagulation is determined by the underlying VTE and not by the presence of the IVC filter itself. Practically speaking, however, many patients who require an IVC filter for recurrent VTE are the same ones who would benefit most from indefinite anticoagulation. In patients who are not able to receive anticoagulants due to recent surgery or trauma, the clinician should continually reassess if anticoagulation may be started safely at a later date.
Placement of permanent IVC filters has been evaluated as an adjunct to routine anticoagulation in patients with proximal DVT.57 Routine IVC filter placement has not been shown to prolong early or late survival in patients with proximal DVT but did decrease the rate of PE (hazard ratio, 0.22; 95% confidence interval, 0.05–0.90), however; an increased rate of recurrent DVT was seen in patients with IVC filters (hazard ratio, 1.87; 95% confidence interval, 1.10–3.20).
IVC filters are associated with acute and late complications. Acute complications include thrombosis or bleeding at the insertion site and misplacement of the filter. Late complications include thrombosis of the IVC, DVT, breaking, migration, or erosion of the filter through the IVC (Fig. 24-9). The rate of fatal complications is <0.12%.58
Preoperative computed tomography imaging and intraoperative photo demonstrating erosion of IVC filter through the IVC wall.
In some patients, the need for an IVC filter may be self-limited. Such patients can be treated with so-called removable IVC filters. Depending on the device, removable IVC filters are potentially removable by percutaneous endovascular techniques for up to several months after their initial implantation assuming the filter is no longer required and does not have large amounts of trapped thrombi. All temporary IVC filters are approved for permanent implantation, and many so-called temporary filters end up as permanent devices with all the potential complications of permanent IVC filters.
Operative Venous Thrombectomy
In patients with acute iliofemoral DVT, surgical therapy is generally reserved for patients who worsen with anticoagulation therapy and those with phlegmasia cerulea dolens and impending venous gangrene. If the patient has phlegmasia cerulea dolens, a fasciotomy of the calf compartments is first performed. In iliofemoral DVT, a longitudinal venotomy is made in the common femoral vein and a venous balloon embolectomy catheter is passed through the thrombus into the IVC and pulled back several times until no further thrombus can be extracted. The distal thrombus in the leg is removed by manual pressure beginning in the foot. This is accomplished by application of a tight rubber elastic wrap beginning at the foot and extending to the thigh. If the thrombus in the femoral vein is old and cannot be extracted, the vein may be ligated. For a thrombus that extends into the IVC, the IVC is exposed transperitoneally and controlled below the renal veins. The IVC is opened and the thrombus is removed by gentle massage. An intraoperative completion venogram determines if any residual thrombus or stenosis is present. If a residual iliac vein stenosis is present, intraoperative angioplasty and stenting can be performed. In most cases, an arteriovenous fistula is then created by anastomosing the great saphenous vein (GSV) end to side with the superficial femoral artery in an effort to maintain patency of the thrombectomized iliofemoral venous segment. Heparin is administered postoperatively for several days. Warfarin anticoagulation is maintained for at least 6 months after thrombectomy. Complications of iliofemoral thrombectomy include PE in up to 20% of patients59 and death in <1% of patients.60
One study followed 77 limbs for a mean of 8.5 years after thrombectomy for acute iliofemoral DVT. In limbs with successful thrombectomy, valvular competence in the thrombectomized venous segment was 80% at 5 years and 56% at 10 years. More than 90% of patients had minimal or no symptoms of PTS. There were 12 (16%) early thrombectomy failures. Patients were required to wear compression stockings for at least 1 year after thrombectomy.61
Survival rates for surgical pulmonary embolectomy have improved over the past 20 years with the addition of cardiopulmonary bypass. Emergency pulmonary embolectomy for acute PE is rarely indicated. Patients with preterminal massive PE (Fig. 24-10) for whom thrombolysis has failed or who have contraindications to thrombolytics may be candidates for this procedure. Open pulmonary artery embolectomy is performed through a posterolateral thoracotomy with direct visualization of the pulmonary arteries. Mortality rates range between 20% and 40%.62,63,64
Autopsy specimen showing a massive pulmonary embolism.
Percutaneous catheter-based techniques for removal of a PE involve mechanical thrombus fragmentation or embolectomy using suction devices. Mechanical clot fragmentation is followed by CDT. Results of catheter-based fragmentation are based on small case series. In a study in which a fragmentation device was used in 10 patients with acute massive PE, fragmentation was successful in 7 patients with a mortality rate of 20%.65 Transvenous catheter pulmonary suction embolectomy has also been performed for acute massive PE with a reported 76% successful extraction rate and a 30-day survival of 70%.66
Patients who undergo major general surgical, gynecologic, urologic, and neurosurgical procedures without thromboprophylaxis have a significant incidence of perioperative DVT. An estimated one third of the 150,000 to 200,000 VTE-related deaths per year in the United States occur following surgery.67 The goal of prophylaxis is to reduce the mortality and morbidity associated with VTE. The first manifestation of VTE may be a life-threatening PE (Fig. 24-11), and as indicated earlier, clinical evaluation to detect DVT before PE is unreliable.
Computed tomography angiogram showing multiple pulmonary embolisms (arrows) (Used with permission from Dr. Scott Ambruster.)
Effective methods of VTE prophylaxis involve the use of one or more pharmacologic or mechanical modalities. Currently available pharmacologic agents include low-dose UFH, LMWH, synthetic pentasaccharides, and vitamin K antagonists. Mechanical methods include intermittent pneumatic compression (IPC) and graduated compression stockings. There is insufficient evidence to consider aspirin alone as adequate DVT prophylaxis. Methods of prophylaxis vary with regard to efficacy, and the 2012 ACCP Clinical Practice Guidelines stratify their uses according to the patient’s level of VTE risk, bleeding risk, and the values and preferences of individual patients (see Table 24-3).
Venous Thromboembolism Prophylaxis in Nonorthopedic Surgery
The risk for VTE associated with a surgical procedure depends on the type of operation, type of anesthesia, duration of surgery, and other risk factors, such as patient age, presence of cancer, prior VTE, obesity, presence of infection, and known thrombophilic disorders. VTE risk can be stratified according to the previously mentioned risk assessment models, the Caprini score and Rogers score. These risk assessment models are included in the prophylaxis guidelines for nonorthopedic surgery (Tables 24-5 and 24-6). A composite score is created using assigned values for each risk factor. The cumulative score for each patient is then used to predict thrombosis risk and provide recommendations regarding VTE prophylaxis.
Table 24-5Risk assessment model from the Patient Safety in Surgery Study ||Download (.pdf) Table 24-5 Risk assessment model from the Patient Safety in Surgery Study
|RISK FACTOR ||RISK SCORE POINTS |
Operation type other than endocrine
Respiratory and hernia
Thoracoabdominal aneurysm, embolectomy/thrombectomy, venous reconstruction and endovascular repair
ASA, physical status classification
3,4, or 5
Two points for each of these conditions
Chemotherapy for malignancy within 30 days of operation
Preoperative serum sodium >145 mmol/L
Transfusion >4 units packed RBCs in 72 hours before operation
One point for each of these conditions
Wound class (clean/contaminated)
Preoperative hematocrit ≤38%
Preoperative bilirubin >1 mg/dL
Albumin ≤3.5 mg/dL
Zero points for each of these conditions
ASA physical class of 1
Work RVU <10
Table 24-6Caprini risk assessment model ||Download (.pdf) Table 24-6 Caprini risk assessment model
|1 POINT ||2 POINTS ||3 POINTS ||5 POINTS |
|Age 41–60 ||Age 61–74 ||Age ≥75 ||Stroke (<1 month) |
|Minor surgery ||Arthroscopic surgery ||History of VTE ||Elective arthroplasty |
|BMI >25 kg/m2 ||Major open surgery (>45 minutes) ||Family history of VTE ||Hip, pelvis, or leg fracture |
|Swollen legs ||Laparoscopic surgery (>45 minutes) ||Factor V Leiden ||Acute spinal cord injury (<1 month) |
|Varicose veins ||Malignancy ||Prothrombin 20210A || |
|Pregnancy or postpartum ||Confined to bed (>72 hours) ||Lupus anticoagulant || |
|History of unexplained or recurrent spontaneous abortion ||Immobilizing plaster cast ||Anticardiolipin antibody || |
|Oral contraceptives of hormone replacement ||Central venous access ||Elevated serum homocysteine || |
|Sepsis (<1 month) || ||Heparin-induced thrombocytopenia || |
|Serious lung disease, including pneumonia (<1 month) || ||Other congenital or acquired thrombophilia || |
|Abnormal pulmonary function test || || || |
|Acute myocardial infarction || || || |
|Congestive heart failure || || || |
|History of inflammatory bowel disease || || || |
|Medical patient at bed rest || || || |
Patients at very low risk (<0.5%; Rogers score <7; Caprini score 0) who undergo general or abdominopelvic procedures do not require pharmacologic or mechanical prophylaxis; however, early ambulation is required. Patients at low risk (<1.5%; Rogers score 7–10; Caprini score 1–2) should receive mechanical prophylaxis. Patients at moderate risk (3%; Rogers score >10; Caprini score 3–4) should receive LMWH at recommended doses, low-dose UFH, or mechanical prophylaxis. Patients at high risk (6%; Caprini score ≥5) should receive LMWH at recommended doses or low-dose UFH and mechanical prophylaxis. Thromboprophylaxis should continue until discharge, except in select high-risk patients with malignancy in whom extended-duration prophylaxis (up to 4–6 weeks) may be beneficial. Patients with significant risk for bleeding should receive mechanical prophylaxis until this risk subsides.67
Overall, low-dose UFH and LMWH reduce the risk for symptomatic and asymptomatic VTE by 60% to 70%. The risks for bleeding differ, depending on the dosage. Lower dosages of LMWH appear to be associated with less bleeding risk than low-dose UFH, but the latter produces less bleeding risk than higher prophylactic dosages of LMWH.68 Other advantages of LMWH include once-daily dosing protocols and a lower rate of heparin-associated antibody formation.
Fondaparinux has been compared with the LMWH dalteparin in patients who undergo high-risk major abdominal surgery. It also has been compared with IPC alone in patients undergoing non–high-risk abdominal surgery.69,70 Fondaparinux demonstrated rates of VTE prevention, bleeding complications, and mortality similar to those of LMWH. It was more beneficial than IPC alone in reducing VTE but with a higher rate of bleeding (1.6% vs. 0.2%).
Prophylactic insertion of IVC filters has been suggested for VTE prophylaxis in high-risk trauma patients, bariatric surgical patients, and some patients with malignancy who have contraindications for LMWH therapy.71 A 5-year study of prophylactic IVC filter placement in 132 trauma patients at high risk of PE (head injury, spinal cord injury, pelvic or long bone fractures) reported a 0% incidence of symptomatic PE in patients with a correctly positioned IVC filter.72 In 47 patients with a malpositioned IVC filter (strut malposition or filter tilt), there was a 6.3% incidence of symptomatic PE with three deaths. DVT occurred at the insertion site in 3.1% of the patients. IVC patency was 97.1% at 3 years.
Fatal and nonfatal PE can still occur in patients with vena cava interruption. As noted earlier, long-term complications associated with permanent IVC filters include IVC thrombosis and DVT. Currently, the ACCP recommends IVC filters be placed only if a proximal DVT is present and anticoagulation therapy is contraindicated. IVC filter insertion is not recommended for primary prophylaxis.67
Removable IVC filters may be placed in patients with a temporarily increased risk of PE.73 The best patient groups for retrievable filter placement may include young trauma patients with transient immobility, patients undergoing surgical procedures associated with a high risk of PE, and patients with hypercoagulable states who cannot receive anticoagulation therapy for a short period of time. Careful follow-up is required to assure all potentially removable filters are in fact removed.