In the United States, each year more than five million patients develop DVT with more than 10% of these patients experiencing PE. It is estimated that as many as 250,000 deaths can be attributed to clot annually. VTE rarely occurs among healthy ambulatory people. Essentially, all victims have easily identified risk factors falling into one of three general categories: stasis of venous blood, injury to the venous intima, and/or hypercoagulability. Thus, increasing age, reduced mobility, pregnancy, previous DVT, trauma (especially to the legs), surgery, severe sepsis, cancer, indwelling venous catheters, chronic obstructive pulmonary disease, and heart failure are common predisposing conditions. The more risk factors present, the higher the likelihood of VTE. In the absence of prophylaxis, some patient groups are at amazingly high risk. For example, VTE incidence is greater than 60% following hip or knee replacement or fracture repair; nearly 40% among ICU patients; 30% in general surgical patients; and at least 15% among general medical patients.

Because it is hard to believe that such a common and important condition could result from such mundane causes, great interest exists in the role of the half a dozen or so, well-characterized thrombophilic (procoagulant) disorders (e.g., factor V Leiden, prothrombin 20210 mutation, anticardiolipin antibodies, homocystinuria or deficiencies of antithrombin, or proteins C or S). Together, the two most common factor V Leiden (activated protein C resistance) and the prothrombin 20210 mutation can be identified in 5% to 10% of the white population. Despite their high prevalence, VTE risk among those affected is low without additional risk factors. Controversy exists regarding the importance of diagnosing thrombophilia, particularly in asymptomatic individuals, and the optimal course of action if diagnosed. Traditional teaching encourages a search for thrombophilia in patients who develop VTE in the absence of other risk factors, especially if young, or when history shows a personal or family history of recurrent thrombosis. Because testing is complex, expensive, and holds lifelong implications for the patient labeled with an “incurable” genetic disease and their family, evaluation should almost certainly be left to a coagulation specialist probably in conjunction with a genetic counselor. Fortunately, there is never an urgency to evaluate patients for these conditions, and their diagnosis does not change the acute VTE treatment. At this time, routine screening of patients with VTE for thrombophilia is not indicated (see Chapter 30).

Traditional teaching holds that near 90% of PEs result from lower extremity DVTs and that the arms and neck are rarely if ever a clot source. However, changes in practice have altered the epidemiology of the disease; now hospitalized patients routinely have upper extremity sources of clot. For example, central venous catheters (including peripherally inserted central lines) are more common than ever and provide a nidus for thrombus formation. Embolization is particularly likely upon catheter removal, as the encasing thrombus is stripped away. It is now estimated that perhaps as many as 30% of fatal PEs stem from catheters. Heparin-bonding may protect temporarily until the anticoagulant is leached out of the catheter over 24 to 36 h. In contrast to
disease of the deep veins, superficial thrombophlebitis manifest by erythema, tenderness, and a palpable “venous cord” poses a low VTE risk and can usually be treated symptomatically. On rare occasions, extension into the deep veins occurs.

The natural history of leg DVT is well characterized. Most clots begin as asymptomatic calf thrombi, hence many physicians regard them as having little importance. Unfortunately, 30% to 50% of these clots propagate above the knee and 30% to 50% of proximal DVTs eventually produce PE. Therefore, between 10% and 25% of untreated patients with calf thrombi develop PE. Surprising to many clinicians is the fact that during life, most acute thrombi in the legs and lungs are asymptomatic and therefore go undiagnosed.

Prevention is the most important treatment of VTE. In fact, deterrence is so important and so often overlooked that it makes sense to institute hospitalwide prophylaxis programs for patients at risk. Fortunately, nearly 90% of United States ICU patients now receive some form of effective prophylaxis compared to just 30% a few years ago. Rates of protection are profoundly lower for hospitalized patients outside the ICU.

Although benefit is unproven for the hospitalized patient, DVT risk might be reduced by ambulation. A corollary is that avoidance of excessive sedation and unnecessary paralysis could reduce risk by shortening periods of immobility. Unfortunately, walking is “ordered” for hospitalized patients far more often than performed, and activity never reaches normal levels. Furthermore, ICU patients rarely walk although it is possible to have selected intubated patients ambulate with portable ventilators. However, even if frequent vigorous walking were conducted, doing so would reverse only one of the numerous VTE risk factors present in most hospitalized patients.

Because of its superior effectiveness, pharmacologic prophylaxis should be provided to inpatients with VTE risk factors unless there is a contraindication to use. Fixed-dose subcutaneous (SC) unfractionated heparin (UFH) reduces DVT risk by as much as 66% in general medical and surgical patients when given thrice daily. Unfortunately, higher risk patients (i.e., critically ill, multitrauma, hip or knee replacement or intra-abdominal or pelvic cancer surgery) do not enjoy the same protection. Those at highest risk should receive an appropriate dose of a low-molecular-weight heparin (LMWH) or fondaparinux; UFH in a dose adjusted to prolong the activated partial thromboplastin time (aPTT) (typically 7,500 to 10,000 units SC every 8 h); or oral warfarin given in a dose and a time frame sufficient to prolong the prothrombin time (PT). Surprisingly, little data support the common practice of administering 5,000 units of UFH every 12 h, even to the so-called low-risk patients. When used in fixed prophylactic doses, UFH and LMWH do not prolong the aPTT or increase serious hemorrhagic complications; however, all heparins and fondaparinux tend to accumulate when glomerular filtration rate falls below 30 mL/min, increasing the likelihood of bleeding (see Chapter 30).

LMWHs equal or surpass the effectiveness of UFH for VTE prophylaxis and have a lower incidence of bleeding and heparin-induced thrombocytopenia (HIT). Overall, LMWHs provide greater than 75% relative risk reduction for DVT formation. High bioavailability (approx. 90%) and longer half-life (4 to 5 h) allow single daily injections for most indications. (After total knee replacement, twice daily injections may be optimal, and there is debate regarding the need for twice daily therapy in the critically ill and obese patient.) Because each LMWH has different pharmacological properties and few head-to-head comparisons have been conducted, LMWHs should not be considered interchangeable. There is little financial incentive to choose one over another, as differences in cost among brands is trivial. To avoid confusion regarding dose and frequency and to control costs, it makes sense to limit the number of prophylactic agents on the formulary. As a result, many institutions select one LMWH with a broad range of indications. The higher costs of LMWHs compared to UFH for prophylaxis seems well worth the investment, given the superior effectiveness, lower incidence of HIT, and reduced number of injections required. The price differential has also dramatically narrowed with recent increases in UFH cost associated with contamination related shortages.

For some orthopedic procedures (e.g., hip or knee replacement), specific protocols using preoperative warfarin have been shown to reduce VTE risk, but rarely in practice are the proven protocols followed. The custom of administering the first warfarin dose the night before, or day of, surgery does not provide effective perioperative prophylaxis—prevention requires an international normalized ratio (INR) greater than 2, a target which typically requires 5 days to achieve.

Fondaparinux is a synthetic factor Xa inhibitor which has been shown to be effective prophylaxis for patients undergoing abdominal, knee, and hip surgery. High bioavailability is advantageous but lack of reversibility, dependence on renal clearance, and the extremely long half-life approximately 17 h are disadvantages. Fondaparinux should not be used in patients with renal insufficiency. Optimism that fondaparinux might not be associated with thrombocytopenia has been undermined by a recent report of HIT. Studies comparing this drug to LMWH demonstrate a slightly higher bleeding risk, but a slightly lower DVT risk (with a low overall clot risk for both agents) results that are not surprising, given that fondaparinux was administered closer to the time of surgery. There does not appear to be a convincing advantage of fondaparinux over an appropriately selected LMWH.

Dextran, aspirin, and other NSAIDs, and dipyridamole should be avoided because they have not been shown to be as effective as UFH, LMWH, fondaparinux or warfarin prophylaxis, and in the case of dextran, a higher risk of bleeding is seen.

Custom-fitted, elastic, graded compression stockings and pneumatic compression devices are options for patients at unacceptable risk for bleeding if given anticoagulants (e.g., coagulopathy, trauma, or neurosurgery). Interestingly, the mechanism of action of these mechanical devices is probably not the mere squeezing of blood from the legs, but in part an antithrombotic and profibrinolytic effect induced by vascular endothelial compression. Alone, each device has been shown to reduce the risk of DVT, with even lower rates observed when they are used concurrently. At a 30% relative risk reduction for custom-fitted elastic stockings and a 50% relative risk reduction for pneumatic compression devices, neither is as effective as pharmacologic prophylaxis. Because of patient discomfort or through sheer forgetfulness, these devices are often not worn at all or are applied inconsistently. Furthermore, elastic stockings often fit poorly because they are rarely custom manufactured. Obviously, if malfitting or not worn, neither device offers protection. In addition, the effectiveness of lower extremity mechanical devices to reduce the risk of upper extremity (often catheter related) DVT is questionable.

The signs of DVT relate to venous inflammation and obstruction. Unilateral lower-extremity erythema, warmth, swelling, edema, and pain suggest DVT. The Homans sign is a nonspecific indicator of calf inflammation seldom present in documented DVT. Unfortunately, the physical examination is poor for detecting DVT and distinguishing it from common mimics.

Several common conditions mimic DVT. A ruptured Baker’s cyst presents as a mass in the calf with pain and erythema, usually in patients with rheumatoid arthritis. An accurate diagnosis must be made to avoid the use of potentially dangerous therapies (e.g., thrombolytic drugs) that could provoke bleeding into the cyst. Rupture of the plantaris tendon also may mimic DVT on examination, but the history is key, revealing recent exertion with the acute onset of pain. Crystalline arthritis (gout or pseudogout) may produce intense joint space inflammation that extends into the calf. Cellulitis, especially that seen in the setting of direct trauma or chronic fungal infection of the feet or after coronary bypass surgery, often is confused with DVT. It is frequently so difficult to distinguish DVT from cellulitis that concomitant antibiotic and anticoagulation therapy are begun empirically until DVT is confirmed or excluded. Although sometimes confused with DVT, pulmonary osteoarthropathy presents with pain, tenderness, and swelling over the anterior tibia, with or without clubbing, and can be confirmed radiographically. In patients with hemophilia or those taking anticoagulants, hematoma formation in the calf muscles also may produce a syndrome clinically similar to DVT. Postphlebitic syndrome (deep venous insufficiency) develops to some degree in nearly half of all patients after a DVT. The syndrome, which typically becomes fully manifest over 3 to 5 years, can be a particularly confounding problem because the recurrent discomfort and swelling that occurs often prompts frequent DVT reevaluations.

Because the physical examination is insensitive and nonspecific, a confirmatory study is necessary in essentially all cases. Although immensely popular, the d-dimer is of little or no diagnostic value in hospitalized patients because its concentration is increased by essentially every critical illness (e.g., stroke, severe sepsis, trauma, surgery, pregnancy, liver failure, myocardial infarction). This differs from the outpatient setting where a negative d-dimer is common, and when a negative result is paired with a low validated risk score (e.g., Wells criteria) the likelihood of clot is so small no additional testing is indicated.

Ultrasound (US) is capable of imaging veins and probing venous flow. When noncompressible clot is imaged, the diagnosis is all but certain. Doppler studies can reliably confirm obstruction, unless flow is compromised by low cardiac output or high intra-abdominal or central venous pressures. In such cases, low flow may be reported but clot will not be seen. US is not as sensitive as contrast venography for detecting calf clot and may miss some clots restricted to the pelvis. Portability, low cost, and unquestioned safety make US the preferred first test in the ICU population despite these limitations.

The contrast venogram is simultaneously the most sensitive, definitive, time-consuming, and potentially injurious method for detecting DVT. An advantage to venography is its ability to visualize thrombus from the feet to the vena cava. Venography also occasionally helps distinguish acute thrombosis from chronic thrombosis based on appearance of the clot and is immune to false positive results brought about by low flow states. Because contrast may precipitate renal insufficiency and cause allergic reactions and phlebitis, venography is most appropriate when US is technically limited.

In up to one third of cases of angiographically proven PE, studies for DVT are negative. This situation could be because all leg clots have embolized to the lung or the legs were not the source of the PE. Although a negative leg US or venogram does not exclude a diagnosis of PE, in almost all cases a positive study permits VTE treatment to be initiated without additional testing.