Deep venous thrombosis. The dilemma of diagnosis

Abstract

Despite advanced medical technology, deep venous thrombosis continues to be a seriously underdiagnosed common postsurgical complication of the patient, particularly of lower extremity procedures, often requiring postoperative bed rest as in any routine podiatric surgery. Deep venous thrombosis and its complication, pulmonary embolism, are elusive clinical conditions since patients often tend to exhibit neither specific nor reliable signs or symptoms. However, the suspicion of the surgeon, generally based on subtle clinical manifestations, is the most important step in the diagnosis. Diagnosis will never be made unless he or she entertains the possibility. Since prevention of the potentially fatal outcome of pulmonary emboli secondary to deep venous thrombosis and possibly the serious morbidity caused by long-term sequelae in the lower extremity is now possible, the importance of an early, adequate diagnosis is indisputable. Diagnosis on clinical grounds alone is notoriously unreliable and objective tests are necessary to avoid overtreatment or undertreatment.

Definition and Epidemiology

Thrombophlebitis is the presence of a thrombus of fibrin clot in a vein. Its associated local symptoms are caused by an inflammatory reaction incited by the adherence of the thrombus to the venous wall (a process that takes approximately 4 or 5 days). Local symptoms may be minimal or absent when the thrombus does not adhere well, extending primarily into the free-flowing circulation [1]. Thrombi may occur in any vein, but the term “deep venous thrombosis” refers mainly to thrombi located in the deep leg veins, beginning in the soleal arcade of the calf muscle and extending into the popliteal, superficial femoral, common femoral, iliac veins, and inferior vena cava. It also includes thrombi of the pelvic venous network and major veins of the upper extremities. Thrombi originating in the major deep veins usually begin at the base of the valve pockets and extend proximally [2]. Venous thrombi arise at bifurcations or valve cups. The two most important valves for controlling venous hydrostatic pressure are the valve of proximal superficial femoral vein, and the valve of the distal popliteal vein [3].

Studies indicate that 20% to 50% of patients undergoing orthopedic or major surgery requiring postoperative bed rest develop deep venous thrombosis. Half of these develop within the first 24 hr after surgery, and the rest within 7 days. Approximately 50% of these patients have bilateral surgery. The original thrombus occurs in the calf vein in 90% of patients developing deep venous thrombosis, of which approximately 20% will propagate proximally into the major deep vessels of the thigh, where approximately half will eventually embolize. Fifty percent of the thrombi are spontaneous in the area of surgical trauma [4]. In total hip replacement, deep venous thrombosis develops in 40% to 60% of untreated patients, whereas proximal venous thrombosis occurs in 20% to 40% of the same patients, all of which eventually result in a fatal pulmonary embolism in 1% to 3% of the untreated cases [5].

Pathogenesis

The three major recognized factors in the etiology of deep venous thrombosis are as follows: local injury to vessels (injured endothelium), venous stasis or turbulence of blood flow, and alternation (hypercoagulability) of the blood itself [6].

Endothelial injury can be caused by factors such as surgery, trauma, central venous access catheters, pacemaker wires, and previous thromboembolic events. Injury of the endothelial surface of the vessel results in platelet and fibrin adherence to the subendothelial collagen. Release of adenosine diphosphate from damaged endothelial cells and red blood cells, adherent platelets, augments the buildup of the platelet clump. Although this initial aggregation of platelets is reversible, irreversible aggregation quickly develops with the addition of thrombin formation by the activation of factor XII by exposed collagen (intrinsic pathway), and the release of thromboplastin from injured endothelium (extrinsic pathway). Other factors such as catecholamines, serotonin lysosomal enzymes, intraplatelet fibrinogen, and polymerizing fibrin are also speculated to be involved.

The development of large, thrombotic masses probably requires vessel injury, along with alternation in vessel blood flow. In veins, stasis most probably plays a dominant role over turbulence; although it is not the sole etiologic factor. Experiments by Wessler [7] on isolated veins required hypercoagulability, in addition to stasis, to induce thrombi. As studies indicate, venous stasis might be caused by factors such as prolonged immobilization, debilitating medical conditions, stroke, myocardial infarction, heart failure, obesity, varicose veins, anesthesia, and age (particularly if older than 65 years of age).

However, venous stasis generally occurs in bedridden patients. Those at bed rest because of myocardial infarction have a 17% to 38% chance of developing deep venous thrombosis [8]. Furthermore, hypercoagulation can be caused by various factors such as hyperviscosity, increased platelet adhesiveness, malignant disease, high estrogen level, thrombocytosis, antiphospholipid syndrome, increased clotting factors, and fibrinogen [3]. The natural history of venous thrombi may include: 1) propagation and eventual vascular obstruction with resulting distal venous congestion and increased collateral blood flow; 2) embolization; 3) fibrinolytic dissolution (first 2 days); and 4) organization and recanalization (weeks to months).

In the past, symptomatic thrombophlebitis was considered more benign than silent thrombosis, since it was believed that inflammation was likely to induce firm attachment of the thrombus to the vessel wall, therefore reducing the risk of embolization. However, there has been no statistical evidence to support this argument, and since it is now evident that the development of inflammation is secondary to the presence of the thrombus and is not a primary inflammatory vascular disease causing thrombosis, there is no significant pathophysiologic distinction between thrombophlebitis and silent thrombosis.

Risk Factors

Specific risk factors, or predisposing conditions include the following: advancing age, oestroprogestogens, tumors, venous insufficiency, menopause, previous diagnosis of thromboembolism, recent history of trauma, surgery, heart failure, shock, malignant disease, infection, inactivity, or obesity (especially in association with trauma or surgery), diabetes, peripheral arterial disease, pregnancy or oral contraceptive use, hypercoagulable states resulting from metabolic disease or malignancy (especially pancreas, stomach, and lung), and inherited disorders such as antithrombin III deficiency, low plasminogen level, and abnormal fibrinogen level [9]. The highest risk occurs probably in patients undergoing reconstructive, or total hip replacement. In hip fractures, approximately 75% of pertrochanteric and 35% of subcapital femoral neck fractures result in deep venous thrombosis. Hip or knee replacement operations have a postoperative risk of deep venous thrombosis of 40% to 70%, and hospital trauma victims in general have a 2% risk of pulmonary embolism, where approximately 50% of such cases become fatal. Patients with hip fractures also have the highest risk of thromboembolism; approximately 38% to 50% of deaths after hip fracture were caused by pulmonary embolism [10].

Stroke, however, with hemiplegia of lower extremity has a 60% deep venous thrombosis rate, whereas acute myocardial infarction has a 30% to 40% rate. The risk of thrombosis clot propagation and embolization is doubled in older patients, who develop shock or congestive heart failure in association with myocardial infarction. Furthermore, certain plausible physiologic reasons may help to explain why sitting still for long periods, particularly in cramped conditions (such as in most aircraft), might predispose to venous thromboembolism. However, the report of the in-flight emergencies or deaths, and of deaths in airports, will tend to underestimate the importance of venous thrombolism as a hazard of air travel [11].

Presentation

Deep venous thrombosis is an acute, obstructive disease, with symptoms ranging from the minimal to the dramatic. Signs and symptoms of deep venous thrombosis are absent in approximately 50% of the patients, yet range from subtle to obvious in the other 50%. Classically, the patient has an edematous limb with an erythrocyanotic appearance, with dilated superficial veins and elevated skin temperature. The presence of all four signs can be very specific for deep venous thrombosis; however, the absence of clinical signs should not preclude the diagnosis [3].

Superficial thrombophlebitis results in local inflammation with erythema, pain, and tenderness along the course of a vein, and is often palpable. Mildto-moderate edema can accompany this also. Deep venous thrombosis, on the other hand, is more variable in its clinical presentation. In its most common form, known as the milk leg, marked swelling of the leg becomes apparent because of the obstruction of the deep venous circulation, and the entire lower extremity is swollen, pale, and cold; generally caused by reflex arterial spasm. Tenderness in the area of the clot, as well as distally, may occur. Typically, the pain worsens with motion and dependency, improving only with rest and elevation. Pain alone, however, is a rather unreliable sign, while unilateral swelling is much more suggestive. Calf pain produced by dorsiflexion of the foot (Homans’ sign) is a classic finding, but is only approximately 50% accurate and is often lacking.

Manifestations of possible pulmonary emboli, such as tachypnea, dyspnea, tachycardia, fever, cough, pleurisy, chest pain, hemoptysis, pleural effusion, and chest x-ray evidence of pulmonary infarction, will often lead to diagnosis of a deep venous thrombosis that has embolized. Approximately 90% of the patients with postoperative pulmonary emboli have a documentable deep venous thrombosis. The most common clinical condition that stimulates a deep venous thrombosis and causes diagnostic confusion is cellulitis. Other entities in the differential diagnosis of deep venous thrombosis include muscle cramps and tears, tenosynovitis, hematoma, ruptured Baker’s cyst, edema (either on the basis of lymphatic obstruction or organ system failure, ie, cardiac, renal, or hepatic), and postphlebitic syndrome.

Diagnosis

The lack of reliable clinical findings creates much difficulty in the diagnosis of deep venous thrombosis. Clinical examination reveals 50% of deep venous thrombosis, at most, and falsely suggests the diagnosis approximately 30% to 60% of the time [12]. Once the clinician is alerted to the possibility of deep venous thrombosis, various diagnostic procedures may be carried out. Accurate diagnosis, however, is facilitated by knowing the most common sites of thrombus formation, the likelihood of propagation, the type of patients at high risk, signs and symptoms, and proper testing.

1) Doppler Insonation. Doppler technology is based on changes in soundwave frequency, varying with the rate of vascular flow, known as the Doppler shift. The specific venous flow changes occur during and after a Valsalva maneuver and are accompanied by a Doppler shift. Impaired blood flow will result in the absence of a Doppler shift and of the expected flow acceleration after a Valsalva maneuver. A Doppler study has a 90% sensitivity per proximal deep venous thrombosis, and 50% sensitivity for calf pain thrombi. Nonocclusive thrombi result in a false-negative study, whereas external venous compression, poor patient positioning, and other causes of collapsed deep veins result in a false-positive study. The technique is highly operator-dependent [3]. Nevertheless, it is a noninvasive test that is portable and accurate, if the technician is well trained and experienced.

2) The sphygmomanometer cuff pain test of Lowenberg may prove to be useful, particularly when carried out during ambulation. A blood-pressure cuff around the involved part of the extremity is inflated to 200 mmHg, and then deflated. During inflation, discomfort is normally experienced at approximately 160 mmHg or above; normally in venous obstructive disease, discomfort or tenderness is evident at a much lower level (approximately at 60 mmHg to 150 mmHg). The test may often be positive when other symptoms and signs are absent; nevertheless, it is not sufficiently specific to be considered diagnostic.

3) Radioiodinated Fibrinogen Scan. Iodine 125, labeled fibrinogen, is injected intravenously and corporated into thrombi; it is then detected externally with a radiation counter throughout 1 to 10 days. If local activity increases at approximately 15% or more, from one day to the next, or from one leg to the other, or if “hot spots” occur, this is read as a positive result. Sensitivity of this test is approximately 92%. False-negative results occur at proximal sites, where a greater blood pool increases the background activity and increases soft tissue mass, resulting in the masking of the activity. False-positive results may occur in situations where there is fibrinogen turnover and fibrin deposition, such as surgical wounds, skin ulcers, varicose veins, cellulitis, hematoma, and any type of inflammation.

4) Impedance Plethysmography. Impedance plethysmography is based on the electrical conduction of the blood. The amount of blood in an extremity is inversely related to the impedance to the electrical conduction. A cuff is used to impede venous drainage. The outflowing venous blood from the lower extremity is translated into an electrical tracing that shows a gradual rise in the volume of the leg, and, when the cuff is released, a rapid fall in volume. With obstruction of the venous system, this fall is less pronounced and less rapid than in the normal situation. This method is 95% sensitive and 98% specific for proximal thrombi. However, the sensitivity drops to 30% in the calf. False-positive results can be derived from arterial insufficiency, increasing venous pressure as in congestive heart failure, and venous constriction associated with shock and external venous compression. False-negative findings result from nonocclusive thrombi and old thrombi with collateral circulation. Although this method is operatordependent, it is straightforward and easy to perform and learn. Its best attribute may be its ability to conduct serial examinations. In addition, it is noninvasive, portable, quick (compared with venography), and low-cost technique [3].

The combination of impedance plethysmography and radioactive fibrinogen scanning has been reported to be effective for detecting deep venous thrombosis in symptomatic patients. However, a recent report concludes that it is not reliable for screening in asymptomatic high-risk patients, such as those undergoing hip replacement [13].

5) Ultrasound Imaging. These methods are now being tested as screening methods. They are noninvasive, and evolving technology is continuously creating improved images.

a. B-Mode Ultrasound. This method involves the visualization of the vessel wall as a Doppler signal to indicate flow. Interpretation is based mainly on the compressibility of the vessel lumen under direct visualization, with confirmatory information coming from assessment of the flow characteristics within the vessel. This method of screening compares favorably with venography in the detection of deep venous thrombosis.

b. Duplex Imaging. It combines Doppler ultrasound and B-mode (two-dimensional) imaging to allow visual assessment of the vessel in conjunction with the Doppler flow signal. Adding color flow capabilities to the ultrasound image may improve vein visualization [13]. This method is noninvasive and can therefore be performed serially; however, it is a timeconsuming test that occasionally takes approximately 30 to 60 min and requires a skilled technician, and is also expensive. Nevertheless, the accuracy of this test is indisputable [10].

c. Color Duplex Flow in Imaging. This is a further refinement of ultrasound technique. In this method, flow rates within the vessel are translated into corresponding colors. Absence of visible flow indicates a thrombus, with confirmatory information coming from intraluminal echogenecity, vein distention, and absence of normal vein compressibility. Color duplex flow imaging is reported to be a useful method of primary imaging for deep venous thrombosis [13].

6) Venography. Venography is the tracing of the venous pulse, and is generally considered the gold standard for diagnosis of deep venous thrombosis. In this process, iodinated dye is injected distally and visualized with x-ray. Proper mixing of blood and contrast material, which have different viscosities, is required to minimize artifacts. The thrombus, therefore, can be visualized either as a constant filling defect, or more indirectly as an abrupt termination of the opacified vessel, nonopacification of vessels or abnormal flow patterns, suggesting collateralization. These indirect signs may also be seen in cellulitis, edema, and hematoma. In 3% to 4% of patients with negative venographic study, a later fibrinogen 125 study is positive. In 1% to 2% clinically, obvious thrombosis develops, presumably, as a side effect of the irradiating dye, although these figures may include false-negative venography results [14]. Side effects of venography include urticaria, flushing and sensation of warmth, nausea and vomiting, metallic taste, myalgia, and anaphylaxis. The postvenographic pain syndrome that consists of muscle pain, swelling, and tenderness (believed to be caused by the hyperosmality of the contrast media) may occur in as many as 25% of patients, often lasting up to 36 hr. Dilution of the contrast medium with normal saline, addition of a local anesthetic such as lidocaine, and flushing of the vein with saline after contrast injection are helpful in minimizing these reactions [8].

If well performed, venography tends to be very accurate and capable of detecting thrombi at all levels. However, it is an invasive procedure that requires the use of a radiology suite, which, in turn, makes it moderately expensive. It is unpleasant for the patient, is time consuming, and can actually cause deep venous thrombosis. It is, therefore, not practical in numerous follow-up studies, and many physicians are reluctant to order such a test for patients with minimal physical findings. Nevertheless, phlebography continues to have a major role in cases where noninvasive testing is equivocal, or inaccessible [15].

Treatment

Precluding this comprehensive review of deep venous thrombosis, a sample case study will be given. Although this seems a somewhat rare postoperative complication in the patient, special attention should be made to prevent the more deadly pulmonary embolism.

A 5l-year-old male presented to the office, who had had a base wedge osteotomy to correct his hallux valgus deformity on his right foot. A below the knee nonweightbearing cast was applied and it was decided to keep the patient as an inpatient for 3 days. The patient’s hospital course was unremarkable until the third postoperative day, when the patient noted that pain and tenderness were evident in his right lower extremity. He described the pain as an aching discomfort, usually intermittent, and aggravated by weightbearing. The patient stated that bed rest and analgesics provided the greatest relief.

Physical examinations revealed typical signs indicative of deep venous thrombosis. There was mild edema in the right lower extremity, especially the lower thigh and knee region. Measurements with a type measure showed the right lower thigh to be almost 3 cm greater in circumference than the contralateral limb. The right lower thigh and knee region appeared erythematous or even reddish-purple. Active dorsiflexion of the right ankle (Homans’ sign) elicited pain, as did compression of the posterior calf muscles. Differential diagnosis could indicate the following: superficial thrombus, cellulitis, ruptured Baker’s cyst, muscle tear, muscle cramp, tumor, hematoma, lymphedema, congestive heart failure, and postphlebetic syndrome. Subsequently, diagnostic tests were undertaken to confirm the suspicion of deep venous thrombosis. The first examination performed was a Doppler ultrasound. During this noninvasive technique, it was found that there was distortion of venous flow pattern around the area of the popliteal vein. However, to diagnose deep venous thrombosis, a venography examination was performed. This technique is the most reliable and is considered the gold standard for detecting deep venous thrombosis. It can give excellent visualization of the deep calf veins: the popliteal, the femoral, and the external and common iliac veins. A filling defect in the right popliteal vein was noted on venogram studies.

Treatment of this problem was quickly rendered. The patient’s internist was consulted and the patient was transferred to their services. The patient was then placed on heparin and Coumadin^® (Dupont Pharma, Wilmington, DE) therapy. Additionally, the patient was placed in the antiembolic position, making sure that the lower extremities were above the patient’s heart. Furthermore, compression stockings were applied to both lower extremities. The patient was encouraged to wear the stockings beyond the duration of the thrombotic treatment, in order to prevent any further occurrence of deep venous thrombosis. Treatment with Coumadin continued for approximately 6 to 8 weeks.

Deep venous thrombosis treatment begins with creating an environment that minimizes the chance of complications. The patient should be placed in the antiembolic position (hips and knees flexed approximately 30°, with legs elevated higher than the level of the heart). Dependency of the lower extremity is avoided, therefore decreasing stress on an incompetent valvular system, but also decreasing stasis.

Warm, moist heat should be used to promote venous dilation, increased capacitance, therefore increasing blood flow around the thrombosis. The patient also needs to be well hydrated through intravenous or oral fluids. Analgesics may be needed for pain management.

Treatment of deep venous thrombosis is crucial since venous thromboembolism may ensue. Recommending a suitable preventive measure, therefore, greatly depends on the ability to recognize patients at high risk for such a condition. Prophylactic measures may include the administration of anticoagulants, or intermittent pneumatic compression of the legs. Other recently adopted techniques, such as newly developed antithrombotic agents, modified vena caval interruption device, and improved thrombolytic regimens, have been introduced for purposes of both treatment and prevention. The proper prophylactic measures would dramatically reduce the morbidity and mortality rates associated with venous thromboembolism, especially in postoperative patients. These methods should begin at the time of the patient’s admission to the hospital, and be continued until he or she is fully ambulatory.

In cases where thrombosis has occurred, these measures are not adequate to prevent further clot propagation or embolization; therefore, full-dose anticoagulant therapy is needed.

The anticoagulant therapy is usually introduced by the use of intravenous heparin. It is usually achieved by either a continuous drip, or an intermittent injection; preferably the former. Inadequate anticoagulation, however, is a major continuing problem in the first few days of heparin therapy; hence, the clotting time is monitored with the objective of maintaining it at approximately twice the normal time. The activated partial thromboplastin time has generally supplanted the clotting time as a measure of heparin dosage. Published guidelines for monitoring and dosing adjustments have been designed for the purpose of driving the activated partial thromboplastin time rapidly into the therapeutic range of greater than 1.5 and less than 2.5 times the control value. If heparin is administered intravenously, a loading dose of 5,000 U followed by a maintenance dosage of 1,300 U/hr is recommended, and if given subcutaneously, a starting dose of 17,500U every 12 hr is recommended. With either regimen, the goal is to keep the activated partial thromboplastin time prolonged beyond 1.5 times the control value. The activated partial thromboplastin time can be assessed 4 to 6 hr after the therapy is initiated and the dosage is adjusted. In cases where patients appear to be at high risk for bleeding, a loading dose of 5,000 U followed by a maintenance dosage of 1,000 U/hr may be administered.

Heparin is usually continued for 7 to 14 days, followed by one of the coumarin drugs. Since at least 48 hr must transpire before a significant effect on the clotting mechanism is observed, whichever drug is selected is administered several days before heparin is to be discontinued. Stopping heparin abruptly may be followed by a rebound increase in clotting potential; therefore, the dose is gradually reduced over a 48-to-72-hr interval. The coumarin drugs are continued for a variable time, usually 3 months. The prothrombin time is used to adjust dosage, and is optimally kept at twice the normal dose.

An alternative is warfarin sodium, which has proven effective when started on the day of surgery. The dosage is 10 mg on the first and second days, followed by the estimated daily maintenance dosage of 5 mg. The dosage is adjusted in such manner as to prolong the prothrombin time to an international normalized ratio of 2 to 3 by the third to fourth postoperative days. This corresponds to a prothrombin time ratio of 1.3 to 1.5 with typical rabbit brain thromboplastin, or a prolongation of 16 to 18 sec with a control value of 12 sec.

When warfarin is started on the same day as heparin, the estimated daily maintenance dosage is 4 to 5 mg, or in a loading dosage of 10mg/day on the first and second days, followed by the estimated daily maintenance dosage of 4 to 5 mg on the third day. Heparin and warfarin should be administered jointly for a minimum of 4 to 5 days; if the prothrombin time is in the therapeutic range (international normalized ratio of 2.0 to 3.0) without heparin by the fifth day, then the drug can be discontinued and warfarin alone maintained. However, in patients with massive pulmonary embolism or extensive iliofemoral thrombosis, a minimum of 4 to 5 days of combination therapy with heparin and warfarin is still necessary.

One of the setbacks of anticoagulant therapy, especially in the use of heparin sodium, is the development of thrombocytopenia in as many as 5% of patients, which, in turn, requires prompt monitoring of the patient’s platelet count every day. Immunemediated thrombocytopenia should be suspected when the patient’s platelet count falls precipitously, or in a sustained manner below 100,000/uL, in which case heparin has to be stopped immediately. This syndrome is associated with platelet and endothelial injury and can lead to a platelet predominance, or white thrombus in the arterial system, with recurrence and extension of venous thromboembolism. The consequences include stroke, loss of limb, or death [2]. If the risk of recurrent embolism appears low and warfarin sodium given for several days has resulted in a prothrombin time within the therapeutic range, this drug can be continued without additional interruptions. The therapeutic range of warfarin therapy for venous thrombolism is a prothrombin time ratio of 2 to 3 with the international standard human brain thromboplastin, the basis for international normalized ratio. Therefore, knowing the international normalized ratio is vital during the course of a successful treatment and without such information and knowledge, the patient’s risk for recurrent thromboembolism increases tremendously, either from under anticoagulation or from excessive bleeding secondary to over anticoagulation. Currently, the recommended period for warfarin in the treatment of venous thrombolism is 3 months. However, in patients with ongoing risk factors such as malignancy or other causes of hypercoagulability, warfarin may be administered indefinitely [2].

Drugs that increase the anticoagulant effect of warfarin include: Oral antibiotics and antifungal drugs, chloral hydrate, clofibrate, diazoxide, phenylbutazone, salicylates, sulfonamides, sulfonylureas, alcohol (acute ingestion), allopurinol, chloramphenicol, cimetidine, trimethoprim-sulfamethoxazole, disulfiram, methylphenidate, metronidazole, phenylbutazone, sulfinpyrazone, acetaminophen, anaboloic steroids, clofibrate, danazol, erythromycin, gemfibrozil, glucagon, influenza virus vaccine, ketoconazole, sulindac, and thyroid drugs [16].

Drugs that decrease the anticoagulant effect of warfarin are: barbiturates, carbamazepine, glutethimide, griseofulvin, nafcillin, phenytoin, estrogens, oral contraceptives, vitamin K (including nutritional supplements), aluminum hydroxide, cholestyramine, colestipol, ethchlorvynol, griseofulvin, sucralfate [17].

Since diet and numerous medications and health conditions can alter an individual’s response to warfarin, routine monitoring of the patient’s prothrombin time may be necessary. A new finger-stick method for monitoring prothrombin time called Coumatrak^® (Consolidated Technologies, Inc, Austin, TX) may allow more efficient and less costly management of outpatient anticoagulant therapy.

Typically, the adverse effects of warfarin are mainly associated with hemorrhagic complications, often precipitated by additional medications, systematic illnesses, especially those resulting in hepatic dysfunction and poor patient nutrition, leading to vitamin K deficiency. Meanwhile, warfarin-induced skin necrosis sometimes occurs 2 to 5 days into the course of oral anticoagulation; therefore, the overlap of warfarin and heparin is important to prevent such complication.

Thrombolytic Therapy

According to the National Institutes of Health, heparin therapy fails to: 1) eliminate the source of an embolus; 2) improve the hemodynamic disturbances associated with the thromboembolic event; 3) prevent vascular damage in the deep veins, which could result in chronic venous insufficiency; and 4) prevent permanent pulmonary vascular damage that could lead to pulmonary hypertension [16].

Thrombolytic therapy has been used along with the standard anticoagulant therapy to treat deep venous thrombosis and pulmonary embolism. However, the response to thrombolytic therapy for venous thromboembolism is highly variable. Patients who respond best are those with massive fresh thromboses, documented by venography, preferably less than 7 days old, who do not seem to be at high risk for bleeding.

Currently, streptokinase, urokinase, and tissue plasminogen activator are approved for treatment of pulmonary embolism; and streptokinase, which is an indirect activator of plasminogen resulting in fibrin degradation, is approved for the treatment of deep venous thrombosis. However, streptokinase will act on both fibrin-bond and free plasminogen, resulting in a state of fibrinolysis and may result in severe hemorrhagic complications. Tissue plasminogen activator, produced by recombinant DNA technology, is fibrin specific and does not significantly activate free plasminogen in the circulation and will probably be the preferred thrombolytic agent when widely available. If thrombolytic therapy is chosen, giving it early is advised and invasive procedures must be minimized.

Optimal doses of thrombolytic agents in venous thromboembolism have not been reached; however, accepted regimens are as follows: 1) urokinase, 4.400 U/Kg/hr after an intravenous bolus of 4,400 U/Kg; 2) streptokinase, 100,000 U/hr after an intravenous bolus of 250,000 U; 3) tissue plasminogen activator, 0.06 mg/Kg/hr for deep venous thrombosis, or 100 mg over a 2- to 3-hr period for pulmonary embolism.

A serious issue regarding the use of thrombolytic therapy is usually the cost of each agent. Although the cost varies in each procedure, streptokinase is often the preferred choice, since it is readily cheaper than both urokinase and tissue plasminogen activator. Absolute contraindications to thrombolytic therapy are active internal bleeding and severe cerebrovascular or intracranial procedure within the previous 2 months. Relative contraindications, on the other hand, include coagulopathy, pregnancy, severe hypertension, serious trauma, organ biopsy, cardiopulmonary resuscitation with rib fracture, invasive diagnostic procedure, or if the patient is within 10 days of a major surgery.

Intravenous streptokinase followed by heparin is an alternative to heparin alone in patients with deep venous thrombosis, with the clot being fresh and located in the popliteal area or higher, resulting in rapid clot lysis, that has been shown to help maintain venous valvular anatomy and function in an effort to decrease the incidence of post-thrombotic syndrome [18]. Although few studies have somewhat demonstrated favorable results, such ability of thrombolytic agents has not been well documented.

For treatment of deep venous thrombosis, a loading dose of 25,000 U of streptokinase is administered over approximately 30 min, followed by a maintenance drip of 100,000 U/hr, resulting in a lytic state in 90% of patients. Treatment is maintained for 24 to 72 hr at which time it will be followed by heparin therapy as soon as the thrombin time is less than 2 hr control. Prior to the initiation of the therapy, however, a full coagulation profile should be included in the laboratory work-up. Furthermore, it should also be composed of a complete blood count to check for thrombocytopenia, as well as a urinary analysis to check for hematuria. In order to determine the presence or absence of a lytic state during the treatment, a thrombin time scan should be performed. It is then checked 4 hr after the start of the therapy, at which time any significant prolongation reveals adequate lysis; where any further dosage manipulation is generally not required. Overdosage of streptokinase can result in binding of all available prominogen, where a lytic state will not be achieved, since there will be no plasminogen available for activation.

Side effects include severe bleeding, often requiring blood transfusion (4%), fever (20%), and allergic reactions (6%). Nausea, vomiting, headaches, and myalgia may also occur, and rarely anaphylaxis. One hundred mg of hydrocortisone intravenous prior to therapy may minimize these side effects. In case of life-threatening hemorrhage, aminocaproic acid is used to reverse the lytic state. Embolic migration, however, is another problem often posed by the use of thrombolytics.

Other Methods

Treatment of deep venous thrombosis and therefore prevention of pulmonary embolism can be attained through surgical or percutaneous interruption of the inferior vena cava. Generally accepted indications for vena caval interruption procedures include: 1) the high-risk patient or those with acute venous thromboembolism in whom anticoagulation is contraindicated; 2) recurrence of thromboembolism despite adequate anticoagulation; and 3) surgical pulmonary embolism.

The preferred surgical procedure appears to be the insertion of a filter through the internal jugular or the femoral vein. The newest version of the filters can be inserted percutaneously with minimal trauma, and have a long-term patency rate exceeding 95%.

Patients with phlegmasia cerulea dolens (a type of severe venous thrombosis) may benefit from thrombectomy; however, it is preferred to try thrombolytic therapy first. Pulmonary thrombectomy should be reserved for patients who fail to respond to aggressive thrombolytic therapy, and for hemodynamically unstable patients in whom thrombolysis is contraindicated.

Prophylaxis

Early postoperative ambulation is practiced whenever feasible. In fact, there are a number of methods for deep venous thrombosis prophylaxis. Low-dose subcutaneous heparin at 5,000 U every 8 to 12 hr is effective and currently the most popular method for the prevention of deep venous thrombosis. Intermittent pneumatic leg compression prevents venous stasis by increasing flow in the deep veins of the leg. It is also effective (significantly weaker than warfarin therapy in preventing proximal venous thrombosis after total hip replacement procedures, while being more effective in preventing calf vein thrombosis) and is more acceptable to a greater number of surgeons who fear bleeding complications from lowdose heparin. Oral anticoagulants have been used but have a high risk of bleeding complications. The two-step warfarin method designed to decrease the risk of bleeding was shown to be effective in hip and knee replacement patients. Dextran, a glucose polymer originally developed as a volume expander, has been found to be an effective prophylactic agent because it decreases blood viscosity while reducing platelet interaction, making the thrombus formed more susceptible to fibrinolysis. Because it is a volume expander, it should be administered with caution in elderly patients, or those with congestive heart failure. An adjusted dose of subcutaneous heparin started 2 days prior to the operation, and continued for 7 to 9 days postoperatively, is designed to maintain the activated partial thromboplastin time 31.5 and 36 sec [10].

Long-Term Complications

The most important acute complication of deep venous thrombosis is pulmonary embolism with its attendant morbidity and mortality. Pulmonary embolism is the third leading cause of death in the US. Approximately 650,000 Americans experience symptoms each year, and 10% of them die within the first hour of the appearance of the symptoms. However, deep venous insufficiency or occlusion, or both, are much more common long-term problems and many venous ulcers occur each year, putting strain on both the work force and the health service resources. It has long been recognized that deep venous thrombosis is usually followed by recanalization of the veins and that this process results in the destruction of the venous valves, which, in turn, causes deep venous insufficiency. Failure to recanalize results in chronic venous occlusion. This is the fundamental abnormality that results in a postphlebic limb with venous ulceration or venous claudication.19 Post-thrombotic syndrome is an important long-term sequela of deep venous thrombosis characterized by failure of the calf muscle pump, pain, edema, skin and soft tissue changes, and ulceration. Vigorous prevention is unquestionably vital [10].