Deep Vein Thrombosis
Deep vein thrombosis (DVT) is the primary cause of fatal and nonfatal pulmonary embolism (PE). Most thrombi form in the deep calf veins – in the valve sinuses of the soleal veins or behind the valve cusps in the posterior and anterior tibial veins. However, 20% or more develop in the popliteal vein, femoral vein, and iliac branches, and more than 95% of pulmonary emboli originate in these more proximal deep veins of the lower extremities. Preventing the development of proximal DVT is clinically important since fatal PE occurs primarily as a complication of DVT in the proximal veins. In addition, isolated calf thrombi, when left untreated, may propagate proximally, resulting in the possibility of significant emboli.
Because patients with DVT and/or PE may be asymptomatic or present with nonspecific findings, clinical diagnosis can be difficult. However, waiting until thromboembolism is clinically evident before starting treatment can place patients at increased risk. Up to 90% of deaths due to PE occur within one to two hours of the event, thus accurate diagnosis and appropriate therapy often is not possible. Yet, when left untreated, the mortality rate of PE is between 25% and 30%.
Thus, preventing DVT from occurring is the most effective method of preventing PE, and appropriately treating DVT that has already formed is the best way of minimizing the frequency of PE. By following this therapeutic strategy, particularly with patients who are known to be at increased risk for developing DVT and PE, the risk of embolism and its serious consequences can be significantly reduced.
Risk Factors Associated With DVT
Being able to anticipate the possible occurrence of DVT is an important part of prevention. This is best accomplished by recognizing the presence of known factors that put patients at increased risk for DVT. Although the development of DVT has primarily been associated with various surgical procedures, there are a number of other clinical factors that increase the risk of DVT. In addition, some patients may have “hypercoagulable” states that predispose them to the formation of DVT.
Clinical Risk Factors
Clinical factors that are known to increase the risk for DVT are shown in Table 1. These clinical risk factors are considered to be additive (ie, the more risk factors patients have, the greater their chances of developing DVT). Patients can be classified based on the presence of known risk factors, and appropriate preventive measures taken, depending on the patient’s “risk” classification. Table 2 is an example of such stratification for surgical patients.
Patients considered to be among the highest at risk of developing DVT are those who have major orthopedic surgery, especially total hip replacement (THR) and total knee replacement (TKR). Following major orthopedic surgery of the lower extremities, DVT is the most common early serious complication. Patients who suffer major trauma, especially trauma that causes head injury or fracture of the spine, pelvis, hip, femur, or tibia, are also at increased risk of venous thrombi. DVT is also a frequent complication of other major surgeries (eg, abdominal, thoracic, genitourinary, and neurosurgery) and prolonged immobilization, regardless of the underlying medical condition, particularly in elderly patients. Other factors associated with increased risk of DVT are listed in Table 1. A previous history of venous thrombosis is considered to be one of the strongest indicators that a patient will develop DVT in the future.
Patients with certain congenital (primary) or acquired (secondary) abnormalities of the blood coagulation system are also predisposed to increased risk of venous thrombosis. Referred to as “hypercoagulable” states, these disorders affect the normal physiologic balance between coagulation and fibrinolysis (Table 3). Congenital hypercoagulability is associated with an inability to deactivate coagulation or activate fibrinolysis. Acquired hypercoagulability disorders are more common but not as well understood. A number of causes are believed to be involved, including hyperviscosity, increased circulating procoagulant factors, and inactivation of elements which alter the coagulation/fibrinolysis balance.
Although identifying patients with hypercoagulable states is important because of the significantly increased risk for DVT when other clinical risk factors are present, general screening for primary or acquired conditions is not considered cost-effective. However, testing younger patients who have had one or more thrombotic episodes, or a familial history of thromboembolic disease, may be beneficial in determining if they have an existing congenital hypercoagulable condition. These patients can then be more carefully followed in the future whenever they are at increased risk of developing DVT.
Pathogenesis of Postoperative DVT
Venous stasis, injury to the endothelium of the vein, and hypercoagulability (ie, Virchow’s triad) are the primary elements that predispose patients to postoperative venous thrombosis. It is believed that these three factors are interrelated in the formation of thrombi. Injury to the endothelium of the vein exposes collagen, which results in platelet aggregation and release of tissue thromboplastin. Then, in the presence of stasis and/or hypercoagulability, the coagulation mechanism is activated.
With surgical patients, venous stasis is considered the most important factor in the development of DVT. Stasis occurs during anesthetic administration, during the operation, and postoperatively. With the induction of general anesthesia, vascular tone is significantly reduced and there can be a 50% decrease in blood flow through the popliteal, femoral, and iliac veins. Prolonged immobility during surgery and the postoperative period is also a key factor. As a result of venous stasis, blood stagnates in the calf veins and the valve pockets of the popliteal and femoral veins.
Direct and indirect damage to the endothelium of the vein during surgery is also responsible for much of the risk of postoperative DVT. At the beginning of the operation, damage to the wall of the veins can occur as a result of the surgical incision. During surgery, veins may be twisted and damaged, and the endothelium disrupted. Injury to the endothelium can also occur in collapsed vessels when the intimal walls are in contact, and additional damage can be seen when hypoxemia is present secondary to venous stasis.
Alterations in the normal coagulation/fibrinolysis balance also occur during the perioperative period that can produce a hypercoagulable state. Hypercoagulation can be due to surgical stress. During surgery, the clotting cascade is activated in response to blood loss. After surgery, fibrinolysis is inhibited, particularly in the veins of the lower extremities. Increased plasma viscosity, decreased RBC deformability, and diminished venous blood flow also contribute to a hypercoagulable state during the postoperative period.
Pathophysiology of DVT Formation
The development of thrombi within veins can be regarded physiologically as an exaggeration of the usual hemostasis process. When normal endothelium is disrupted, subendothelial structures trigger a response in platelets, coagulation proteins, and adjoining endothelial cells. Inflammatory reaction in the wall of the vein may be minimal or it may be distinguished by granulocyte infiltration, loss of endothelium, and edema.
Thrombus development begins with platelets aggregation and formation of a nidus (white thrombus). Tissue thromboplastin is released which promotes the formation of a large fibrin clot (red thrombus) through a cycle of continued accumulation and successive layering of platelets and fibrin. RBCs are then trapped and become interspersed within the fibrin. As the thrombus becomes organized, it leaves behind a fibrotic zone that becomes re-endothlialized. Large, extensive thrombi can develop rapidly within minutes. The thrombus tends to propagate proximally in the direction of blood flow as a red thrombus (the primary morphologic venous lesion).
A propagating thrombus may extend into the lumen without causing occlusion, or it may become attached to the opposite wall and occlude the vein, resulting in interruption of blood flow, retrograde thrombosis, and signs of venous stasis in the extremity. In slightly more than half of cases, the thrombus propagates without occluding the vein. However, it can form a long floating “tail” that may break loose and migrate proximally, eventually creating the risk of pulmonary emboli. This series of events is considered the most serious feature of DVT since major PE can occur as a result, without any warning signs or symptoms at the originating site of the thrombus. This embolic risk is highest during the first few days after DVT formation.
Clinical Symptoms and Signs
Clinical diagnosis of DVT is difficult and unreliable. Most hospitalized patients at risk for venous thrombosis have clinically “silent” DVT and are asymptomatic. The classic symptoms and signs of DVT – leg pain, heat, erythema, and swelling – are often absent. It has also been noted that more than 50% of symptomatic patients with suspected DVT based on clinical examination do not have a confirmed diagnosis of thrombus when objective testing (eg, venography) is performed. Accurate diagnosis can be even more difficult with surgical patients, because the postoperative symptoms and signs may be attributed to the trauma of the operation. However, despite the unreliability of clinical manifestations, there are signs and symptoms that can help increase suspicion of the presence of thrombi. These manifestations will depend on the site of the DVT.
DVT Of The Calf Veins
When thrombosis is confined to the calf, clinical diagnosis is particularly difficult because at least three main veins drain the lower leg. DVT in one vein will not result in significant obstruction to venous return, which is maintained through the remaining unaffected veins. Thus, there is no swelling, cyanosis of the skin, or dilated superficial veins. The most common complaint is soreness or pain when standing or walking, which is usually alleviated with rest and elevation of the leg. Although deep calf tenderness may be elicited on physical examination, it is often difficult to differentiate from muscle pain. Homan’s sign (ie, pain or increased resistance during dorsiflexion of the foot) is unreliable in the diagnosis of DVT. It is only an indication of muscular irritability due to edema within the confines of the deep muscular fascia.
DVT Of The Calf And Popliteal Veins
When DVT is localized to veins of the calf and the popliteal veins, the most common patient complaint is calf pain. Physical examination may reveal posterior calf tenderness, skin warmth, increased tissue turgor, slight swelling at the level of the ankle, and, in rare cases, a palpable cord.
DVT Of The Distal Femoral Vein
When DVT is present in the distal portion of the femoral vein and there is associated thrombosis of the more distal veins (ie, popliteal and calf veins), swelling extending to just above the level of the knee is usually present. Physical examination may elicit popliteal and calf tenderness.
DVT Of The Proximal Veins
When there is deep thrombosis of the proximal femoral vein or iliac veins (the iliofemoral system), the calf veins are frequently involved. Unilateral swelling may extend from the inguinal ligaments to the foot. Swelling of the thigh indicates obstruction of the iliofemoral system. If the patient’s thigh measurements are the same, swelling of the calf indicates obstruction of the popliteal and femoral veins. Tenderness is usually present in the groin, popliteal area, and calf along the course of the involved vein. A hard cord may be palpable over the involved vein in the femoral triangle in the groin, the medial thigh, or popliteal space. There also may be warmth, erythema, increased tissue turgor, dilated superficial veins, and the presence of prominent collateral veins.
Extensive venous thrombosis of the deep veins of the thigh and pelvis may result in phlegmasia alba dolens (white or milk legs), which is characterized by pain, noticeable pitting edema, blanching, and pallor. If the thrombosis becomes larger and the obstruction increases, a condition referred to as phlegmasia cerulea dolens (blue leg) may occur. The leg will have a cyanotic color (due to deoxygenated hemoglobin in stagnant veins) and the patient will experience a loss of sensory and motor function. These signs indicate a very serious condition, but fortunately develop in less than 10% of patients with DVT.
The presence of known risk factors, symptoms and signs associated with DVT, and indications of PE help in determining the possibility that a patient may have DVT. However, for a more conclusive diagnosis, invasive and noninvasive procedures are normally required.
Ascending contrast venography is considered the most accurate diagnostic test for detecting distal and proximal DVT and verifying the degree of involvement. Definitive confirmation can be acquired of occlusive and nonocclusive thrombi. However, the test is invasive and may be limited by technical and logistic factors. The patient usually needs to be moved to a radiographic suite for the procedure. Although complications are rare, there may be adverse reaction to the contrast medium and local irritation of the venous endothelium resulting in post-venography phlebitis can occur. Other disadvantages of the procedure include some degree of patient discomfort, the use of ionizing radiation, and that it is more expensive than other tests. Thus, repetitive use of contrast venography is not practical for screening for DVT.
Venography can also be performed with isotope injection and scanning of the leg with a gamma scintillation camera to record the flow of the isotope. This method does not provide the resolution of contrast venography but it is less painful and quick, and can be used for sequential studies. It also avoids the risk of thrombogenesis (which is sometimes associated with injection of contrast medium) and is a useful alternative for patients who are sensitive to contrast media.
Doppler ultrasound, of which compression ultrasound is the mainstay of diagnosis, distinguishes flow abnormalities that occur when the deep veins are obstructed. The test is especially helpful in detecting obstruction of the popliteal vein and those veins proximal to it. However, the test is less helpful in visualizing more distal veins and it is not of benefit in detecting DVT in calf veins, as these do not result in obstruction of venous return. A negative ultrasound examination of the leg, by itself, does not completely eliminate the possibility of DVT when there is clinical suspicion of thromboembolism.
The application of color flow Doppler imaging (CFDI), which visualizes the direction and velocity of movement of blood flow in the veins, may enhance the sonographic examination. It has been reported to be quite accurate in the identification of venous thrombosis and allows for evaluation from the calf veins to the iliac system.
When examining symptomatic patients, compression ultrasound can accurately detect DVT in the popliteal and femoral veins. CFDI has also been reported to improve the diagnosis of calf vein thrombosis in symptomatic patients. However, asymptomatic patients present a different, more demanding diagnostic situation. In these cases, the thrombi are likely to be smaller and visualization of nonocclusive, small thrombi is more difficult with ultrasound.
Duplex ultrasound scanning is a subjective method of testing that is very much dependent on the operator’s expertise. CFDI studies can also be technically compromised by the patient’s postoperative condition. This can include limb swelling, the presence of hematomas, and tenderness in the operated limb. However, because of its accuracy, noninvasive nature, and reduced cost, duplex ultrasound scanning is often the first screening modality used for detecting suspected DVT, even though venography is considered the “gold standard” of the various diagnostic procedures. In many instances, simple compression B-mode ultrasound is the initial diagnostic test of choice.
Impedance plethysmography (IPG), which measures the volume changes in the leg during temporary occlusion of the venous system, is noninvasive and reasonably accurate in detecting obstruction of the proximal veins due to DVT occlusion. However, when the thrombus does not completely occlude the vein and the patient is asymptomatic, the test’s sensitivity is reduced. In addition, IPG is not useful in diagnosing calf vein thrombosis. In the past, IPG was the noninvasive test of choice, but Doppler ultrasound is now considered a better diagnostic modality. IPG and ultrasound often are used in conjunction to improve screening accuracy. If both tests are negative but DVT is still suspected, venography should be performed. Serial IPG may be useful for monitoring distal thrombi that could propagate proximally, thereby increasing the chances of detecting DVT that may cause PE. Serial IPG has also been combined with lung scanning to enhance noninvasive screening of suspected PE.
In 1986, the Consensus Conference of the NIH strongly recommended that prophylactic treatment be administered to all high-risk patients, in particular those who had undergone lower extremity orthopedic surgery, to prevent the occurrence of DVT and PE. Although there is general agreement with the concept of this policy, as of yet, there has been no consensus as to the optimum means of accomplishing this goal. Both mechanical and pharmacologic approaches are available and have been studied extensively.
For patients at low risk of DVT, early mobilization, elevation of the lower extremity, graduated compression elastic stockings, and continuous passive motion (CPM) may be beneficial. However, this is not the case for those at high risk. The benefits of early ambulation in minimizing or eliminating postoperative venous stasis and preventing development of venous thrombi are often thwarted because patients simply take short walks to a nearby chair and sit down – at which point, the leg veins are susceptible to even more stasis. Postoperative use of elastic compression stockings to increase venous return velocity in the legs and exercise via CPM have also been reported to have minimal impact on the incidence of DVT and PE.
Intermittent Pneumatic Compression (IPC): IPC prevents venous stasis and increases fibrinolytic activity. The pneumatic compression devices can be used effectively with most patients with essentially no risk of bleeding or other significant complications. IPC can be used intraoperatively to reduce the risk of venous thrombosis developing during general anesthesia. Postoperatively, IPC can be continued (or started) in the recovery room, and may be used in conjunction with anticoagulation therapy to improve prophylaxis in high-risk patients. It can also be beneficial in preventing DVT formation in patients in whom even low doses of anticoagulants are contraindicated or when the drugs are not effective.
A-V Impulse System: The use of a foot pump (eg, A-V impulse system) produces intermittent external compression to the sole of the foot, which flattens the plantar arch and stimulates the physiologic venous pump in the foot. The mechanism simulates the hemodynamic effects of walking. In a study comparing the A-V impulse system with heparin, significantly fewer thrombi were reported in patients using the foot pump. Although the A-V impulse system has been recommended as a preventive measure for orthopedic patients, additional studies are needed to compare its efficacy and safety with other prophylactic means.
Pharmacologic agents for preventing DVT include aspirin, dextrans, adjusted low-dose warfarin, low-dose and adjusted-dose unfractionated heparin (UFH), and fractionated or low-molecular-weight heparin (LMWH). Combining pharmacologic and mechanical prophylaxis (eg, an anticoagulant along with the use of IPC, compression stockings, or foot pump) may provide better protection than either approach alone for patients who are at significantly high risk of developing DVT and PE.
Aspirin: Reports on the benefits of using aspirin (antagonists that prevent platelet aggregation) to reduce the risk of venous thromboembolism are inconclusive or negative. Aspirin has been reported to have limited efficacy in reducing DVT among general orthopedic patients, but it was noted that other more efficacious pharmacologic agents are available. The pervading consensus is that aspirin has not proven to be effective in preventing DVT in high-risk patients and is not recommended for prophylactic purposes for patients having THR or TKR surgery.
Dextrans: Continuous intravenous (IV) infusion of dextran decreases the incidence of thrombosis through a variety of effects on platelets and clotting factors. Dextran inhibits platelet adhesiveness and aggregation induced by injury to the endothelium of the vein. European investigators have reported that dextrans are effective in reducing the incidence of thromboembolism in high-risk postoperative patients. Others, however, have found the preparations to be only moderately efficacious, and no better or even less effective than warfarin, low-dose heparin, or LMWH.
In addition, the use of Dextran may be associated with significant side effects. These include hemorrhagic complications, plasma volume overload (which can result in CHF and pulmonary edema in older patients}, allergic reactions ranging from mild skin rashes to anaphylactic shock, and, occasionally, renal dysfunction. Although these potentially adverse effects may limit the use of dextrans, they may be an option for some high-risk orthopedic patients. If used, infusion should be started preoperatively before anesthesia is induced with a dose of 500 mL administered over a 4-hour time frame. After surgery, the patient is given 500 mL per day until fully ambulatory.
Adjusted Low-Dose Warfarin Therapy: Use of warfarin is considered an effective form of preventive treatment in decreasing the incidence of postoperative DVT in high-risk patients. Previously, warfarin was usually administered so that the prothrombin time (PT) was maintained within 15-20 sec. Today, low-dose warfarin protocols that maintain the PT between 14-16 sec have been found to be just as effective, with reduced risk of bleeding. For high-risk patients, it is recommended that the PT be prolonged by 3-4 sec, or to an international normalized ratio (INR) of 2.0-3.0. Careful laboratory monitoring can reduce the risk of bleeding complications.
For prophylactic use, there are two way in which warfarin can be administered to patients. In the two-step perioperative regimen, warfarin is given preoperatively in doses that maintain the PT between 1.5-3.0 sec above normal at the time of surgery, and continued postoperatively with dosages that increase the PT ratio to 1.3-1.5 (ie, INR of 2.0-3.0) times the postoperative control value.
Evidence supports the effectiveness and safety of perioperative use of adjusted low-dose warfarin for prophylactic therapy in high-risk patients. However, there has not been universal acceptance of this prophylactic approach for a number of reasons. The perioperative regimen is considered impractical by some surgeons because of the need for a period of preoperative stabilization (usually 2 weeks), the added requirement for careful daily laboratory monitoring to maintain optimum control of the PT, and the increased risk of hemorrhage and excessive bleeding during surgery.
The second method of prophylaxis is to wait until after surgery before administrating warfarin to the patient. This approach reduces the risk of perioperative bleeding and minimizes the chances of late postoperative thromboembolic complications.
: A 5000-unit subcutaneous (SC) dose of UFH is administered 2 hrs before surgery, after which 5000 units is given q 8-12 hrs postoperatively for 6-7 days or until the patient is fully ambulatory. With this regimen, activated partial thrombo- plastin time (APTT) does not need to be monitored because the low doses do not change the laboratory clotting profile. However, this dosage is not completely risk free, as impaired wound healing and thrombocytopenia have been observed.
For patients undergoing a number of elective major operations (ie, general, thoracic, abdominal, and urologic surgery), low-dose heparin therapy is usually effective in reducing the risk of DVT and PE. However, it has not been found as beneficial for patients who undergo orthopedic procedures (particularly THR and TKR). In studies comparing low-dose heparin with placebo, the former did not significantly reduce the frequency or decrease the extent of DVT. For these patients, fixed SC low-dose heparin is considered to be of limited value in preventing postoperative DVT and inferior to other prophylactic measures. In addition, the rate of wound hematoma is higher with use of low-dose heparin. Thus, patients who have prosthetic implants may be at increased risk of infection secondary to a regional hematoma.
: With this prophylactic therapy, the APTT is maintained in the upper limit of normal range (eg, 31-36 sec, or 1-2 sec longer than the control value). Beginning 2 days before surgery, 3500 units UFH SC is administered q 8 hrs. The APTT is measured 6 hrs after the last heparin injection, and the doses are adjusted as needed before and after surgery in order to maintain the APTT at the desired level. This approach has been reported to decrease the incidence of distal and proximal DVT, and appears to provide better protection than low-dose heparin in high-risk patients. In addition, no increase has been observed in the number of wound hematomas or transfusions over that of low-dose heparin therapy. However, while adjusted-dose heparin therapy may be effective, it can be time consuming and laborious because of the required serial APTT laboratory measurements. This is one reason why there has not been universal acceptance of this regimen for DVT prophylaxis.
: LMWH is a relatively new antithrombotic prophylactic option in the United States. LMWH fractions are prepared from standard UFH (average molecular weight of 15,000 daltons) and reduced to mean molecular weights of 4000-6500 daltons.
Compared to UFH, LMWH has a number of potential clinical advantages. These include greater bioavailability (plasma recovery) at low doses, longer plasma half-life, less complicated clearance mechanism, more predictable anticoagulant response when administered in fixed doses, decreased platelet-associated side effects, and reduced frequency of administration with predicable plasma concentrations. Because of these properties, there is no change in platelet function or PT and the APTT remains normal or only slightly prolonged during treatment. Thus, LMWH can be administered without the need for laboratory monitoring of PT or APTT. However, to make sure that thrombocytopenia does not develop, it is recommended that the platelet count is checked before surgery and at least twice after surgery. During the course of therapy, complete blood counts, including hemoglobin, should be routinely performed.
The recommended dosing schedule of enoxaparin (the first LMWH available in the United States for prophylaxis of DVT following elective THR and TKR) is a fixed-dose of 30 mg SC q 12 hrs. The initial dose is administered within 12-24 hrs following surgery, provided that hemostasis has been established.
The usual prophylactic protocol is to continue therapy after surgery until the risk of proximal and distal DVT is reduced. In the past, this has been between 10-14 days for high-risk patients (eg, those who had major orthopedic surgery), with the patients hospitalized and therapy discontinued at time of discharge. However, because today hospital discharges are frequently being made much sooner (often within 4-5 days following surgery), these patients should continue to receive LMWH as a primary prophylaxis on an outpatient basis until the period of greatest risk of developing DVT is concluded (ie, 10-14 days).
Two recent studies have indicated that the postoperative risk of DVT remains significant for high-risk patients longer than previously thought, even when LMWH prophylaxis is used on an inpatient basis and venograms are normal at the time of discharge. Most of the detected thrombi were asymptomatic and detected by routine venography, and their clinical significance is uncertain. However, the findings suggest that continued out-patient prophylaxis is a safe, effective, and rational therapeutic approach for patients who remain at risk of developing thrombi, and may play a significant role in enhancing patient outcome by decreasing the risk of late DVT. With patients being discharged earlier today, this issue is especially relevant. Studies are being conducted to establish which patients are appropriate candidates for this regimen and what the duration protocols should be after patients are discharged. It has been suggested that primary prophylaxis should be continued for 30-35 days after surgery in THR patients.
LMWH’s side effects are comparable to that of UFH but appear to occur less often. Heparin-induced thrombocytopenia has been reported to be lower with LMWH than with UFH, and hemorrhage (the most common adverse reaction observed with LMWH) is less than that of conventional UFH. Finding from numerous studies indicate that LMWH is effective and safe, and more efficacious than other recommended prophylactic approaches in preventing the development of DVT in high-risk patients (eg, following THR or TKR). Pharmacoeconomic studies comparing LMWH with low-dose warfarin and low-dose UFH have reported increased patient-care cost with LMWH, but also a decrease in overall treatment costs when using LMWH based on a lower rate of DVT formation, reduced hospitalization time, and a decrease in patient readmission.
Medical Treatment of Existing DVT
DVT may occur despite preventive measures or because prophylaxis was not employed. If a thrombus is present, the primary goal of medical treatment is preventing PE or minimizing the chances of it occurring. During its initial development, thrombi are often loose and not securely attached to the wall of the vein, which increases the risk of their detaching and propagating to the lungs. Treatment is also directed at fostering resolution of established thrombi, limiting additional thrombus formation, and reestablishing normal venous function to deter chronic venous insufficiency.
Anticoagulation therapy, if not already in progress, is started immediately. After the patient’s leg symptoms (pain, swelling, tenderness) have diminished, he or she is allowed to ambulate; however, standing still or sitting should not be permitted since this can result in increased venous pressure and stasis. Elastic support stockings should be carefully applied to stimulate venous flow.
For proximal DVT, sufficient anticoagulation is the mainstay of treatment. The principal objective is to prevent propagation of the thrombus. By impeding any extension, the body’s endogenous lytic mechanism is able to perform its normal function. If there are no absolute contraindications, heparin is administered immediately, with the goal of reaching an adequate level of anticoagulation as soon as possible (within 24 hrs) to minimize the chance of recurrent throm- bosis. Because of its fast anticoagulant effect (which neutralizes thrombin, suppresses thrombo- plastin, and diminishes platelet activation), heparin is regarded as effective initial therapy. An oral anticoagulant (eg, warfarin) is normally used for long-term protection against recurrent DVT.
Anticoagulant therapy is not indicated for thrombi that remain confined to the calf veins, since no increase in morbidity or mortality has been reported with this approach. However, if serial noninvasive testing (either ultrasound or IPG) detects proximal extension of a thrombus, the patient should be treated with a full course of anticoagulation therapy. Approximately 15%-20% of calf vein thrombi propagate proximally within 10-12 days of their formation, which increases the chances of PE. Thus, if noninvasive diagnostic modalities are not available for serial testing during this acute period, anticoagulant therapy should be started even in asymptomatic patients.
Continuous IV infusion of heparin, delivered and regulated by an infusion pump, is the most commonly used anticoagulant method in North America. This means of administration appears to minimize the total dose needed for control and is associated with less complications. An initial bolus of 3000-5000 units is given intravenously to provide immediate protection against PE and minimize the chances of recurrent thrombi, followed by a continuous infusion of 30,000-35,000 units/day. After the initial bolus, the APTT is checked q 4-6 hrs and the infusion rate is adjusted to maintain the APTT in the therapeutic range (ie, between 1.5-2.5 times the control value). This reduces the risk of bleeding complications while maintaining treatment efficacy. When this therapeutic range has been achieved, the APTT is checked once a day. Full heparin treatment is normally maintained for at least 7-10 days, as this is considered the critical time for dissolution or organization of the thrombus. A longer period of therapy is often recommended for iliofemoral DVT.
Heparin therapy can also be administered by intermittent IV or SC injections. Intermittent IV injections are commonly given in doses of approximately 5000 units q 4 hrs or 7500 units q 6 hrs. However, compared with continuous IV infusion, there is a greater risk of bleeding. In addition, thrombocytopenia can be a frequent and significant side effect. Intermittent SC injections, on the other hand, have been reported effective and safe, and can be administered in a number of different regimens – 5000 units q 4 hrs; 10,000 units q 8 hrs; 7500-12,500 units q 12 hrs; and 20,000 units q 12 hrs. The patient’s APTT is checked after each dose and the subsequent dose is adjusted so that the APTT is maintained between 1.5-2.5 times control value.
LMWH has proven to be effective and safe as a prophylaxis against the development of DVT. Now, recent findings show that LMWH at fixed SC doses is as effective and safe (if not more so) than adjusted-dose UFH in preventing the propagation of established acute DVT and minimizing recurrent thrombi. LMWHs have minimal interaction with platelets, platelet factors, and plasma proteins, and induced thrombocytopenia appears less with LMWH compared with UFH.
Thus, LMWH may be considered as an alternative to standard IV heparin in the initial treatment of established thrombi. In addition, because of the pharmacokinetic properties of LMWH, a new therapeutic approach in the treatment of existing DVT has been advocated. The idea is that these patients can be treated on an outpatient basis at the beginning of LMWH therapy, thereby eliminating the need for the usual 5-10 days hospitalization when using continuous IV therapy.
When heparin therapy is completed, the oral anticoagulant, warfarin, is presently the most common medication used for continued protection of patients with established DVT. Because the full anticoagulant effect of warfarin is delayed, oral therapy is initiated so that it overlaps the use of heparin for at least 5-7 days. Warfarin’s slow onset of action precludes its use as initial therapy for DVT. Because there is no evidence that delaying the onset of warfarin results in a better outcome, it is recommended that therapy be started on day one of heparin therapy.
Warfarin has normally been started at 10-20 mg/day 54. However, new recommendations reduce the initial dose to 5 mg/day, with the dose adjusted to maintain the INR between 2.0-3.0. Before heparin therapy is discontinued, it is important that the patient is in this therapeutic range for at least 3 days. Maintaining an INR of 2.0-3.0 (considered a “less intense” range) has been reported to reduce the risk of major hemorrhagic complications.
How long patients are maintained on warfarin therapy depends on the individual, and whether existing risk factors are reversible (eg, DVT secondary to surgery) or nonreversible. Warfarin therapy is normally continued for 3-6 months, with the INR maintained between 2.0-3.0, to reduce the chance of recurrent thrombi. Patients with acute proximal DVT may need to be treated for up to 12 months. In all cases, noninvasive tests of the leg veins should be conducted before anticoagulation is discontinued and if there is still evidence of thrombi, anticoagulant therapy should be continued.
The use of thrombolytic agents such as streptokinase, urokinase, and TPA, in the general treatment of acute DVT remains undefined. There is no evidence that thrombolytic agents change the short- or long-term morbidity, mortality, or recurrence rates among patients with DVT, or that they are more effective than anticoagulants in preventing PE. If used, they must be followed by a standard course of antithrombotic therapy. At present, thrombolytic therapy has only been recommended in cases of extensive proximal DVT (eg, iliofemoral) and in patients with phlegmasia cerulea dolens for whom anticoagulant therapy has been unsuccessful. The use of thrombolytic agents is contraindicated for postoperative patients.
Surgical Treatment of Existing DVT
Adequate anticoagulation is usually effective in managing DVT. However, if the patients experiences recurrent pulmonary emboli during anticoagulant therapy or if there is absolute contraindication to the use of anticoagulants, surgery may be necessary. There are two surgical approaches to the treatment of existing thrombi.
Interruption of the Inferior Vena Cava (IVC)
The first and most commonly utilized technique is the insertion of an umbrella or vena cava filter in the IVC. The purpose of the filter is to screen out large thrombi migrating to the right heart and reduce the chances of potentially damaging emboli from reaching the pulmonary circulation and causing fatal PE. However, IVC interruption does not prevent formation of DVT or extension of thrombi from their origin in the deep veins; nor does it prevent small thrombi from developing and circulating through the venous system. The procedure should be combined with anticoagulation therapy to prevent development of a thrombus above the filter (which increases the risk of PE) and to help reduce the patient’s risk of developing subsequent DVT. IVC inter-ruption is recommended as the sole treatment only for patients with absolute contraindications to anticoagulation, such as bleeding diathesis or risk of hemorrhage. However, if these contra-indications resolve, anticoagulant therapy should be initiated. Following IVC interruption, the patient usually requires prolonged anticoagulant treatment to treat underlying DVT.
The second surgical option is thrombectomy, the direct surgical removal of thrombi. Although immediate results of this surgical technique can be impressive, longer term postoperative outcomes have not been encouraging and recurrent DVT is common. As a result, thrombectomy is rarely considered in the treatment of DVT. At this time, the procedure is normally reserved for limb salvage in patients with phlegmasia cerulea dolens and potential venous gangrene who have failed to respond to anticoagulant or thrombolytic therapy.
Outpatient and Long-Term Anticoagulant Therapy
Because of today’s increasing tendency to reduce inpatient stay and discharge patients from hospitals sooner, the possible complication of DVT is becoming a more critical problem. Thus it is imperative that appropriate therapeutic measures be taken to make sure that these patients continue receiving optimum protection in the outpatient setting against thrombi development.
Warfarin therapy has been most often used for outpatient and long-term therapy. However, its use requires frequent monitoring and adjustment to maintain the INR in the therapeutic range. In addition, warfarin therapy is contraindicated for some patients. Patients may also being taking other drugs that affect the liver’s metabolism of coumarin or compete for albumin binding sites, which can increase or decrease the efficacy of these medications. Finally, some patients are simply unable to take oral medications.
If oral anticoagulants, such as warfarin, are contraindicated, not appropriate, or inconvenient, patients can be managed with SC UFH injections q 12 hrs. The dose should be adjusted so that the APTT is 1.5-2.5 times the control value. The APTT should initially be measured 6 hrs after the last injection of UFH and adjusted accordingly before the next administration. When the desired dose is achieved, the APTT does not need to be monitored, except during pregnancy when dosage requirements may change. Bleeding and thrombocytopenia are the major complications associated with adjusted-dose UFH therapy. In addition, heparin-induced osteoporosis may occur when therapy is maintained for longer than two months.
Primary prophylactic use has shown that the relatively wide therapeutic range of fixed- dose LMWH, in terms of safety and efficacy, is achieved in almost all patients and eliminates the need for laboratory monitoring. LMWH has also been shown to be effective in the initial treatment of existing thrombi. In addition, studies comparing fixed-dose SC LMWH with adjusted-dose UFH in patients with proximal DVT have concluded that LMWH is a safe, effective, and feasible method of treating these patients on an outpatient basis at home.
The clinical efficacy of LMWH as a secondary prophylaxis (ie, continuing therapy for existing thrombi) is significantly enhanced in the outpatient setting because long-term optimum treatment can be achieved by self-administered SC injections without the need for monitoring. For these reasons, a 3-6 month regimen of LMWH can be an practical alternative to the prevailing 3-6 month warfarin therapy for patients for whom the latter is not a therapeutic choice. Being able to manage most DVT patients at home with LMWH is seen by some as the future in the way thrombosis is treated, resulting in greater clinical utility and cost savings.