Venous Thromboembolism Part 4

Primary prophylaxis

The most effective way of reducing the mortality associated with pulmonary embolism and the morbidity associated with the postthrombotic syndrome is to institute primary prophylaxis in patients at risk for venous thromboembolism. On the basis of well-defined clinical criteria, patients can be classified as being at low, moderate, or high risk for venous thromboem-bolism, and the choice of prophylaxis should be tailored to the patient’s risk [see Table 6]. In the absence of prophylaxis, the frequency of fatal postoperative pulmonary embolism ranges from 0.1% to 0.4% in patients undergoing elective general surgery and from 1% to 5% in patients undergoing elective hip or knee surgery, emergency hip surgery, major trauma, or spinal cord injury. Prophylaxis is cost-effective for most high-risk groups.70

Prophylaxis is achieved either by modulating activation of blood coagulation or by preventing venous stasis by using the following proven approaches: low-dose subcutaneous heparin, intermittent pneumatic compression of the legs, coumarin anticoagulants, adjusted doses of subcutaneous heparin, graduated compression stockings, LMWHs, or fondaparinux.64,70 An-tiplatelet agents, such as aspirin, also prevent venous throm-boembolism but less effectively than the previously stated methods.

Low-dose heparin is given subcutaneously at a dose of 5,000 units 2 hours before surgery and 5,000 U every 8 or 12 hours after surgery. In patients undergoing major orthopedic surgical procedures, low-dose heparin is less effective than warfarin, adjusted-dose heparin, or LMWHs. Intermittent pneumatic compression of the legs enhances blood flow in the deep veins and increases blood fibrinolytic activity. This method of prophylaxis is free of clinically important side effects and is particularly useful in patients who have a high risk of serious bleeding. It is the method of choice for preventing venous thrombosis in patients undergoing neurosurgery, it is effective in patients undergoing major knee surgery, and it is as effective as low-dose heparin in patients undergoing abdominal surgery.


Table 6 Risk Categories for Venous Thromboembolism and Recommendations for Prophylaxis 

High Risk

Moderate Risk

Calf vein thrombosis

30%-50%

10%—30%

Proximal vein thrombosis

10%-20%

2%-8%

Fatal pulmonary embolism

1%-5%

0.2%-0.7%

Recommended prophylaxis

Low-molecular-weight heparin, oral anticoagulants, adjusted-dose heparin, or fon-daparinux

Low-dose heparin, external pneumatic compression, or graduated compression stockings

Graduated compression stockings reduce venous stasis and prevent postoperative venous thrombosis in general surgical patients and in medical or surgical patients with neurologic disorders, including paralysis of the lower limbs.70 In surgical patients, the combined use of graduated compression stockings and low-dose heparin is significantly more effective than use of low-dose heparin alone. Graduated compression stockings are relatively inexpensive and should be considered in all high-risk surgical patients, even if other forms of prophylaxis are used.

Moderate-dose warfarin (INR = 2.0 to 3.0) is effective for preventing postoperative venous thromboembolism in patients in all risk categories.70 Warfarin therapy can be started preopera-tively, at the time of surgery, or in the early postoperative period. Although the anticoagulant effect is not achieved until the third or fourth postoperative day, warfarin treatment started at the time of surgery or in the early postoperative period is effective in patients at very high risk, including patients with hip fractures and those who undergo joint replacement. Prophylaxis with warfarin is less convenient than that with low-dose hep-arin or LMWHs, however, because careful laboratory monitoring is necessary.

LMWH is a safe and effective form of prophylaxis in high-risk patients undergoing elective hip surgery, major general surgery, or major knee surgery, as well as in patients who have experienced hip fracture, spinal injury, or stroke. LMWH is more effective than standard low-dose heparin in general surgical patients, patients undergoing elective hip surgery, and patients with stroke or spinal injury.

In patients who undergo hip or major knee surgery, LMWH is more effective than warfarin but is associated with more frequent bleeding; both of these differences may be caused by a more rapid onset of anticoagulation with postoperatively initiated LMWH than with warfarin. It is uncertain whether the superior efficacy of LMWH over warfarin in the prevention of venographically detectable venous thrombosis is mirrored by fewer symptomatic episodes of venous thromboembolism with LMWH.7072

Fondaparinux was shown to reduce the frequency of veno-graphically-detected DVT by 50% but to cause a small increase in bleeding compared with LMWH in a series of large trials in orthopedic surgical patients.64

Indications for Prophylaxis

General surgery and medicine Low-dose-heparin prophylaxis is the method of choice for moderate-risk general surgical and medical patients. It reduces the risk of venous thromboem-bolism by 50% to 70% and is simple, inexpensive, convenient, and safe.70 If anticoagulants are contraindicated because of an unusually high risk of bleeding, graduated compression stockings, intermittent pneumatic compression of the legs, or both should be used.

Major orthopedic surgery LMWH, fondaparinux, or oral anticoagulants provide effective prophylaxis for venous thrombosis in patients who have undergone hip surgery. Aspirin has also been shown to reduce the frequency of symptomatic venous thromboembolism and fatal pulmonary embolism after hip fracture.71 The relative efficacy and safety of aspirin versus LMWH, fondaparinux, or oral anticoagulants in patients who have a hip fracture or have undergone hip or knee arthroplasty is uncertain. However, because studies have shown that aspirin is much less effective than LMWH or oral anticoagulants at preventing venographically detectable venous thrombosis, aspirin is not recommended as the sole agent for postoperative prophylaxis.70

LMWH, warfarin, fondaparinux, and intermittent pneumatic compression are effective in preventing venous thrombosis in patients undergoing major knee surgery.

Extended prophylaxis with LWMH or warfarin for an additional 3 weeks after hospital discharge should be considered after major orthopedic surgery. Extended prophylaxis is strongly recommended for high-risk patients (e.g., those with previous venous thromboembolism or active cancer).

Genitourinary surgery, neurosurgery, and ocular surgery

Intermittent pneumatic compression, with or without graduated compression stockings, is effective prophylaxis for venous thrombosis and does not increase the risk of bleeding.

Treatment

The objectives of treating patients with venous thromboem-bolism are to prevent pulmonary embolism, the postthrombot-ic syndrome, thromboembolic pulmonary hypertension, and recurrent venous thromboembolism and to alleviate the discomfort of the acute event.

Superficial venous thrombosis usually can be treated conservatively with anti-inflammatory drugs. In patients with DVT, anticoagulants can effectively reduce morbidity and mortality from pulmonary embolism.7 Vena caval interruption, which is usually achieved with an inferior vena caval filter, is also effective but is more complicated, expensive, and invasive and is associated with a doubling of the frequency of recurrent DVT during long-term follow-up.74 For these reasons, it is in general used only if anticoagulant therapy has failed or is contraindicat-ed because of the risk of serious hemorrhage.7

Thrombolytic therapy with streptokinase, urokinase, or rt-PA is more effective than heparin in achieving early lysis of venous thromboembolism and is better than heparin for preventing death in patients with massive pulmonary embolism associated with shock.75 Thrombolytic therapy is therefore the treatment of choice for patients with life-threatening pulmonary embolism.

Thromboendarterectomy is effective treatment in selected cases of chronic thromboembolic pulmonary hypertension involving proximal pulmonary arterial obstruction.76 Urgent pulmonary embolectomy is rarely indicated.

In one study, the routine early use of graduated compression stockings for 2 years reduced the incidence of the postthrombot-ic syndrome by about 50%.9 Consequently, use of graduated compression stockings is recommended for 2 years after proximal DVT, particularly if thrombosis was extensive or associated with marked leg swelling, and if the patient finds the stockings comfortable.

Administration and Dosage Guidelines

Anticoagulant therapy Anticoagulants are the mainstay of treatment for most patients with venous thromboembolism. In the past, the treatment of choice was heparin administered by continuous intravenous infusion or subcutaneous injection, in doses sufficient to produce an adequate anticoagulant response. It is now believed that LMWH administered by subcutaneous injection without laboratory monitoring is as effective and safe as heparin.28

The anticoagulant effect of intravenous heparin or LMWH is immediate. With subcutaneous injection, the anticoagulant effect of both anticoagulants is delayed for about an hour; peak levels occur at 2 to 3 hours. The anticoagulant effect of subcutaneous heparin is maintained for about 12 hours with therapeutic doses. LMWH is effective when administered subcuta-neously once daily.28

Heparin therapy is usually monitored by the aPTT and less frequently by heparin assays, which measure the ability of hep-arin to accelerate the inactivation of factor Xa or thrombin by antithrombin. The anticoagulant effect should be monitored carefully (e.g., every 6 hours until the aPTT is in the therapeutic range, and then daily). The dosage should be adjusted as necessary to achieve an adequate anticoagulant effect because there is a greater risk of recurrent venous thromboembolism if the anticoagulant effect is suboptimal.7 The therapeutic range of aPTT is equivalent to a heparin level between 0.35 and 7.0 U/ml as measured by an anti-factor Xa assay.77 For many aPTT reagents, this range is an aPTT ratio of 1.8 to 2.5 times the mean of the normal laboratory control value.59,77

LMWH is administered subcutaneously on a weight-adjusted basis at a dosage of either 100 anti-Xa U/kg every 12 hours or 150 to 200 anti-Xa units once daily.60 Monitoring is not required.

Treatment with heparin or LMWH is usually continued for 5 to 6 days; warfarin therapy is started on the first or second day, overlapping the heparin therapy (or LMWH) for 4 or 5 days, and is continued until an INR of 2.0 is maintained for at least 24 hours.59 For patients with major pulmonary embolism or extensive DVT, heparin should be given for at least 7 days. A 4- to 5-day period of overlap is necessary because the antithrombotic effects of oral anticoagulants are delayed. The initial course of heparin should be followed by warfarin for at least 3 months.34 Less intense warfarin therapy (INR = 2.0 to 3.0) is just as effective as the high-intensity regimen (INR = 3.0 to 4.5) and produces significantly less bleeding.65 Adjusted-dose subcutaneous heparin or intermediate-dose LMWH can also be used in the outpatient setting,34 but they are more expensive and less convenient than warfarin.

Duration of anticoagulant therapy During the past decade, a series of well-designed studies has helped to define the optimal duration of anticoagulation. The findings of these studies can be summarized as follows:

• Shortening the duration of anticoagulation from 3 or 6 months to 4 or 6 weeks results in a doubling of the frequency of the recurrence of venous thromboembolism during 1 to 2 years of follow-up.

• Patients with venous thromboembolism that was provoked by a transient risk factor have a risk of recurrence about one third lower than those with unprovoked venous throm-boembolism or a persistent risk factor.8,29,31-34

Three months of anticoagulation may not be adequate treatment for an unprovoked (so-called idiopathic) episode of venous thromboembolism; subsequent risk of early recurrence has varied from 5% to 25% per patient-year.8,29,31-34,78

• After 6 months of anticoagulation, recurrent DVT is at least as likely to affect the contralateral leg, which suggests that these recurrences result from systemic rather than local factors (including inadequate treatment).79

• There is a persistently elevated risk of recurrent venous thromboembolism after a first episode; this risk appears to be 5% to 12% per year after 6 or more months of treatment of an unprovoked episode.8,30,31,78

• Oral anticoagulants targeted at an INR of about 2.5 are very effective (risk reduction of 90% or greater) at preventing recurrent unprovoked venous thromboembolism after the first 3 months of treatment.16,80

• Time-limited extensions of anticoagulant therapy beyond 3 or 6 months (e.g., to 12 or 24 months) may delay but not ultimately reduce the risk of recurrent venous thrombo-embolism.30,34,78

Indefinite anticoagulation (i.e., anticoagulation therapy that is not time-limited) is an option for patients who have experienced their first unprovoked venous thromboembolism and who are at low risk for bleeding.34

• A second episode of venous thromboembolism does not necessarily indicate a high risk of recurrence or the need for indefinite anticoagulation.34

Risk of bleeding during anticoagulation therapy differs markedly among patients, depending on the prevalence of risk factors (e.g., advanced age, previous bleeding or stroke, renal failure, anemia, antiplatelet therapy, malignancy, or poor anticoagulant control).34,69

• Risk of recurrence is lower (about half) after an isolated calf (distal) DVT; in such patients, a shorter duration of treatment is appropriate.

• Risk of recurrence is higher with antiphospholipid antibodies (anticardiolipin antibodies or lupus anticoagulants), ho-mozygous factor V Leiden, cancer, and, probably, antithrom-bin deficiency; the presence of any of these factors argues for a longer duration of treatment.15,34

• Heterozygous factor V Leiden and the G20210A prothrom-bin gene mutations do not appear to be clinically important risk factors for recurrence.34

• Other clotting abnormalities (e.g., elevated levels of clotting factors VIII, IX, and XI and homocysteine, and deficiencies of protein C and protein S) may be risk factors for recurrence; they have uncertain implications for duration of treatment.34

Recurrent venous thromboembolism after an initial pulmonary embolism tends to be in the form of another pulmonary embolism (about 60% of cases), whereas recurrent venous thromboembolism after an initial DVT tends to be another DVT (about 80% of cases).81 Consequently, the chance of dying of recurrent venous thromboembolism after anticoagulants are stopped appears to be at least twice as high after a pulmonary embolism as after a DVT; the difference in prognosis may favor indefinite treatment of selected patients after a first unprovoked pulmonary embolism.34

Algorithm for selecting the duration of anticoagulation for venous thromboembolism.

Figure 5 Algorithm for selecting the duration of anticoagulation for venous thromboembolism.

These findings permit the construction of an algorithm for selecting duration of anticoagulation for venous thromboem-bolism [see Figure 5]. Whether anticoagulant therapy (INR = 2.0 to 3.0) is recommended for 3 months, 6 months, or an indefinite period (with annual review) depends primarily on the presence of a provoking risk factor for venous thromboembolism (i.e., major or minor transient risk factor, no risk factor, or cancer), risk factors for bleeding, and patient preference (i.e., burden associated with treatment). Secondary factors are whether the patient has had a previous unprovoked venous thromboem-bolism, whether the venous thromboembolism presented as DVT or as pulmonary embolism, and whether the patient has biochemical risk factors for recurrent venous thromboembolism.

Thrombolytic therapy Thrombolytic therapy produces complete early lysis of acute venous thrombi in 30% to 40% of cases and partial lysis in an additional 30%; in contrast, complete early lysis of venous thrombi occurs in fewer than 10% of patients treated with heparin.7,25,82 The risk of major bleeding, however, is about three times greater with thrombolytic therapy than with heparin.25 The risk of hemorrhage increases with the duration of thrombolytic infusion. Hemorrhage often occurs at a site of previous surgery or trauma. Intracranial hemorrhage occurs in 1% to 2% of patients with pulmonary embolism who are treated with thrombolytic agents, which is a rate about five to 10 times higher than that seen in patients with pulmonary embolism who are treated with heparin.83 Some evidence suggests that thrombolytic therapy with streptokinase reduces the incidence of postthrombotic syndrome,25,82 but data from properly designed trials are lacking. The potential role of thrombolytic therapy in preventing late sequelae of pulmonary embolism is unknown.

Indications for Treatment

Anticoagulant therapy Most patients with proximal vein thrombosis, calf vein thrombosis, or symptomatic pulmonary embolism should be treated first with high-dose heparin or LMWH and then with moderate-intensity oral anticoagulant therapy (INR = 2.0 to 3.0) for at least 3 to 6 months (see above).

Long-term anticoagulant therapy should be considered for patients with malignancy; recurrent unprovoked episodes of venous thromboembolism; unprovoked venous thromboembolism and homozygous factor V Leiden; deficiency of protein C, protein S, or antithrombin; an antiphospholipid antibody; or pulmonary embolism.34 Risk of bleeding and patient preference also strongly influence the decision to use long-term therapy [see Figure 5].

Thrombolytic therapy Thrombolytic therapy is indicated in patients who have major pulmonary embolism with hemo-dynamic compromise (see above). A regimen of 100 mg of rt-PA administered over 2 hours is probably the method of choice because this regimen produces greater lysis at 2 hours than a 24-hour course of conventional urokinase84 and, compared with heparin, produces more rapid clinical improvement in pulmonary vascular resistance and right ventricular function.85,86

The use of thrombolytic therapy in patients who have venous thrombosis is more controversial. Although there is no rigorous supporting evidence for it and it is not part of our clinical practice, regional or systemic thrombolysis may be considered in patients who have large proximal venous thrombi— particularly if the thrombi are confined to the iliac and femoral veins—provided that there are no contraindications.

Absolute contraindications to thrombolytic therapy include active internal bleeding, stroke within the past 3 months, and intracranial disease. Relative contraindications include major surgery within the past 10 days, recent organ biopsy, recent puncture of a noncompressible vessel, recent gastrointestinal bleeding, liver or renal disease, severe arterial hypertension, and severe diabetic retinopathy.

Surgical treatment Pulmonary endarterectomy may be beneficial in selected patients with thromboembolic pulmonary hypertension, which is estimated to occur in about 5% of patients who have undergone treatment of pulmonary em-bolism.76 Urgent pulmonary embolectomy is reserved for patients with a saddle embolism lodged in the main pulmonary artery, those with massive embolism whose blood pressure cannot be maintained despite administration of thrombolytic therapy and vasopressor agents, or those in whom there is an absolute contraindication to thrombolytic therapy.7

Venous Thromboembolism in Pregnancy

The management of venous thromboembolism during pregnancy is complicated because clinical diagnosis is unreliable, some of the objective diagnostic tests are potentially risky to the fetus, and treatment may cause teratogenicity or fetal bleeding.

Diagnosis

In pregnant patients suspected of having venous thrombosis, venous ultrasonography should be used as the initial test.6,88 If the result is abnormal, a diagnosis of proximal DVT is made and the patient is treated with anticoagulants. If venous ultrasound results are normal, we employ IPG or color Doppler to exclude an isolated iliac vein thrombosis. If both tests are normal, either a limited venogram can be performed to exclude isolated calf vein thrombosis, or serial compression ultrasonog-raphy can be performed on two occasions over the next 14 days.6 MRI may also be considered.

The diagnostic approach to pulmonary embolism in pregnancy is similar to that used in nonpregnant patients. Lung scanning and pulmonary angiography can be performed, but the techniques should be modified to reduce exposure of the fetus to radiation.88 Although there is little radiation exposure from ventilation-perfusion scanning, exposure can be reduced further without a serious loss of resolution by administering 50% of the standard dose of radioactive particles for perfusion lung scanning and by limiting ventilation scanning to patients with an abnormal perfusion scan. Fetal radiation exposure from pulmonary angiography can be reduced by using the brachial route for contrast injection and by shielding the abdomen with a lead-lined apron.

Treatment

The treatment of venous thromboembolism is much more complicated in pregnant patients because oral anticoagulants cross the placenta and, if administered during the first trimester, can cause warfarin embryopathy, which is characterized by nasal hypoplasia and skeletal abnormalities.87,88 Warfarin administered during the second and third trimesters can cause dorsal midline dysplasia, abnormalities of the ventricular system, and optic atrophy.

Heparin does not cross the placenta and is much safer than oral anticoagulants during pregnancy. Although there have been reports associating heparin therapy during pregnancy with a high incidence of stillbirth or prematurity, most of these complications occurred in mothers receiving heparin for disorders that are known to be associated with a high rate of fetal loss. Other studies have shown that heparin is safe for the fetus but, when used on a long-term basis during pregnancy, can produce osteoporosis in the mother. The incidence of heparin-induced osteopenia diagnosed by dual-photon absorption x-ray or by conventional x-ray may be as high as 30%, but overt fractures are uncommon, occurring in fewer than 5% of patients. Heparin-induced bleeding is not a common problem during pregnancy, provided that heparin therapy is monitored carefully. The anticoagulant response to heparin can be prolonged if the drug is administered in high doses just before parturition, so there is the potential for local bleeding during and immediately after delivery.87,88

In pregnant patients with acute venous thromboembolism, continuous intravenous heparin or twice-daily LMWH should be administered for 4 to 7 days, followed by subcutaneous hep-arin or LMWH given in adjusted therapeutic doses for the remainder of the pregnancy.89 The injection site should be rotated over the fatty tissue of the lower abdomen and thighs; the site should be compressed for 5 minutes after injection to prevent local bruising. An unwanted anticoagulant effect during delivery can be avoided by discontinuing subcutaneous heparin therapy 24 hours before elective induction of labor.87,88

If there is no evidence of excessive postpartum bleeding, hep-arin therapy can be resumed within 12 hours of delivery and continued until oral anticoagulation is established. The intensity of heparin therapy will depend on the amount of time that has passed since the diagnosis of venous thromboembolism was made: if the diagnosis was made less than 1 month ago, therapeutic doses may be used (with stepwise increases in subcutaneous or intravenous doses over 24 hours); if the diagnosis was made more than 1 month ago, prophylactic or intermediate doses of heparin may be used. Warfarin is started at the same time as heparin and is continued for a minimum of 6 weeks and preferably until patients have received a minimum of 3 months of anticoagulation. Warfarin does not enter breast milk and therefore can be administered to nursing mothers.

Miscellaneous Thromboembolic Disorders thrombosis in unusual sites

Subclavian or Axillary Veins

Thrombosis of the subclavian or axillary veins may be idio-pathic or may occur as a complication of local vascular dam-age.90 It is now most frequently seen as a complication of chronic indwelling catheter use, but it also occurs as a complication after mastectomy and local radiotherapy for breast cancer. Idio-pathic subclavian or axillary vein thrombosis often occurs in young muscular individuals and may be preceded by repetitive, strenuous activity involving the affected arm. Some of these persons have a fixed stenosis of the subclavian vein that is thought to be caused by external compression of the vein as it courses behind the clavicle. Occasionally, subclavian or axillary vein thrombosis can occur in patients with congenital deficiency of antithrombin, protein C, or protein S or in patients with antiphospholipid antibodies. Thrombosis of the axillary or sub-clavian vein or the superior vena cava is a rare complication of an implantable perivenous endocardial pacing system.

Subclavian or axillary thrombosis causes pain, edema, and cyanosis of the arm. In rare cases, the thrombosis extends into the superior vena cava and causes edema and cyanosis of the face and neck. Definitive diagnosis is made by venography or venous ultrasonography.91 Subclavian or axillary vein thrombosis is usually treated with anticoagulants. Regional or systemic throm-bolytic therapy may be considered in young patients without contraindications, because a substantial number of these patients experience aching and swelling when they exert the affected arm.

Mesenteric Vein

An uncommon disorder, mesenteric vein thrombosis usually occurs in the sixth or seventh decade of life. It generally involves segments of the small bowel, leading to hemorrhagic infarction. Affected patients often have associated disorders, such as inflammatory bowel disease, malignancy, portal hypertension, or familial thrombophilia or polycythemia vera, or they may have a history of recent abdominal surgery. In about 20% of cases, no underlying cause is found.

The clinical manifestations of mesenteric vein thrombosis include intermittent abdominal pain, abdominal distention, vomiting, diarrhea, and melena. Diagnosis of mesenteric vein thrombosis is often difficult, but the finding of blood-stained as-citic fluid on abdominal paracentesis or peritoneoscopic evidence of hemorrhagic bowel infarction is characteristic of the disorder. Management includes supportive care and surgical resection, followed by anticoagulant therapy. Mortality is about 20%, and up to 20% of patients experience recurrence.

Renal Vein

Renal vein thrombosis can be idiopathic or a complication of the nephrotic syndrome. Patients may be asymptomatic or may present with abdominal, back, or flank pain and tenderness. Pulmonary embolism is a relatively common complication of renal vein thrombosis. Anticoagulant therapy results in a gradual improvement in renal function, but patients may have long-standing proteinuria. Thrombolytic agents have been used, but the data are inadequate for critical appraisal of this form of treatment.

Thrombophilia

The term thrombophilia denotes any increased tendency to thrombosis, whether inherited or acquired. Thrombophilia is discussed in detail elsewhere [see 5:X1V Thrombotic Disorders].

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