Fang Yin and Jay N. Lozier
This chapter provides guidelines for the treatment of venous thromboembolism (VTE) in patients who require special consideration, such as those who have underlying cancer, malignancy, or who are pregnant. We also discuss use of inferior vena cava (IVC) filters, the prevention, diagnosis, and treatment of postthrombotic syndrome, and anticoagulant drugs with novel mechanisms that are now in development.
PROPHYLAXIS AND TREATMENT OF VENOUS THROMBOEMBOLISM IN THE PATIENT WITH CANCER IN SPECIFIC CLINICAL SETTINGS
Patients with malignancy have an increased risk for VTE due to multiple factors: hypercoagulability resulting from increased production and release of microparticles containing procoagulants such as tissue factor; vessel wall damage, impaired blood flow (stasis) from extrinsic compression; prolonged immobility, anticancer therapy including cytotoxic chemotherapy, certain antiangiogenic agents, or hormonal therapy, and the increasing use of long-term indwelling devices, such as central venous catheters. Tumor angiogenesis, progression, growth, and the metastatic process are enhanced by, and depend on activation of blood coagulation. P-selectin, a cell adhesion molecule has also been identified as a risk factor for recurrent VTE and can be used as a predictive parameter for development of VTE in cancer patients.1 As long as the cancer is active, the increased risk for VTE is present. Cancers most commonly associated with VTE are carcinomas of the pancreas, stomach, kidney, lung, ovary, and bladder, certain hematologic malignancies, cancers of the testis, and gliomas of the brain. Adenocarcinomas appear to be associated with a higher risk than squamous cell cancers.
Studies performed during the current decade have demonstrated that low-molecular-weight heparin (LMWH) is more effective than oral anticoagulants in reducing the risk of recurrent VTE without increasing the risk of bleeding in patients with cancer and acute VTE. Products such as dalteparin, enoxaparin, nadroparin, and tinzaparin as well as the synthetic factor Xa inhibitor, fondaparinux are approved by the Food and Drug Administration (FDA) for the prophylaxis and treatment of VTE. In general, unfractionated heparin (UFH), LMWH, fondaparinux, and oral anticoagulants are the mainstay of therapy. Since LMWH undergoes renal excretion, patients with kidney impairment who receive LMWH should be monitored by measurement of the anti-factor Xa activity. The creatinine clearance should be estimated (or calculated) before initiation of LMWH in elderly patients, since they may have renal dysfunction despite having normal creatinine values. Specific dosing recommendations for enoxaparin in patients with severe renal insufficiency and/or low body weight are presented in Table 23.1. Monitoring of anti-factor Xa levels should also be used in severely obese patients (BMI ≥ 40) who receive therapeutic doses of LMWH and should be considered for those who are obese (BMI ≥ 30), especially if the patient has moderate to severe renal insufficiency (creatinine clearance less than 60 mL/min).2
The target peak anti-factor Xa levels (measured 4 hours after injection) for patients who are treated with LMWH vary according to the product. The target therapeutic range for enoxaparin is 0.6 to 1.2 U/mL for twice-daily dosing and 1 to 2 U/mL for once-daily dosing; for dalteparin the target range is 0.5 to 1.5 U/mL (Table 23.2). Since fondaparinux is produced by complete chemical synthesis and its structure is completely defined, it is dosed on the basis of mass rather than anti-factor Xa activity. The assay for fondaparinux is often reported in terms of its concentration in mass/volume (e.g., mg/L).
Primary Prophylaxis in Cancer Patients Undergoing Surgical Intervention
VTE is a common complication of cancer surgery and the most common cause of death at 30 days after surgery in the @RISTOS prospective observational study of cancer surgery patients.3 Prophylaxis should now be provided routinely to postoperative surgical patients, especially those with underlying cancer. Two randomized controlled trials have demonstrated that extending deep venous thrombosis (DVT) prophylaxis from 1 to 4 weeks reduces the incidence of VTE.4,5 Extended (up to 4 weeks) VTE prophylaxis is recommended for high-risk cancer surgery patients with a previous episode of VTE, anesthesia times longer than 2 hours, advanced stage disease, perioperative bed rest ≥4 days, and patient age ≥ 60 years.3
Laparoscopic surgery is rapidly becoming a common method for tumor resection. It is unclear how the recommendations developed for typical, open procedures should be applied to laparoscopic surgical procedures. Laparoscopic surgery offers the advantage of less tissue disruption, quicker recovery times, and shorter periods of postoperative immobilization. Intuitively the reduction in tissue damage and the possibility of faster mobilization predicts lower risk of thromboembolic complications. Conversely, patients undergoing laparoscopic procedures are subjected to increased venous stasis as a result of the induction of pneumoperitoneum and prolonged use of the reverse Trendelenburg position to visualize and manipulate internal organs.6 The American College of Chest Physicians’ (ACCP) Clinical Practice Guidelines (8th edition) recommend against routine prophylaxis (other than early and frequent ambulation) in patients undergoing laparoscopic surgery without thromboembolic risk factors, and recommends mechanical or pharmacologic prophylaxis in patients with any thromboembolic risk factors.7 The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guidelines for DVT prophylaxis during laparoscopic surgery stratifies inpatients into low, moderate, and high risk groups for thrombosis on the basis of a risk score imputed from the type of procedure and patient risk factors.8,9 Procedure-related risk factors include procedure lasting over 1 hour, and pelvic procedures. Patient-related factors include age > 40 years, immobility, malignancy, thrombophilic states (protein C, protein S, or ATIII deficiency), obesity, peripartum state (or use of estrogens), heart failure, renal failure, varicose veins, inflammatory states, or infection. In the lowest risk group (procedure < 60 minutes in patients with no risk factors) elastic stockings and early ambulation is all that is recommended, and UFH or LMWH is optional. In the moderate-risk group (one patient risk factor in a procedure of less than 60 minutes, or any procedure > 60 minutes with no patient risk factors) pneumatic compression devices or prophylactic heparin or LMWH are recommended. In the high-risk group (two or more risk factors in procedures >60 minutes) a combination of serial compression devices and prophylactic UFH or LMWH are recommended.8,9
Once-daily LMWH appears to be as safe and effective as multiple daily injections of UFH and provides convenience as well as a better quality of life for the patient.3,4 In the Clinical Center at the National Institutes of Health, enoxaparin is the LMWH most commonly employed. However, fondaparinux or other LMWHs, such as nadroparin, dalteparin, ardeparin, tinzaparin, and reviparin, may be considered equivalent. The administration of warfarin at a low, fixed dose (e.g., 1 mg/day) has not been shown to be of value for VTE prophylaxis, and is not recommended.
Primary Venous Thromboembolism Prophylaxis in Cancer Patients Receiving Chemotherapy, Hormonal, and/or Antiangiogenic Treatment
Patients with cancer who are undergoing treatment should be considered for VTE prophylaxis if they have one or more of the following: a history of VTE, a large mass compressing a major vessel, or treatment which includes tamoxifen/raloxifene, diethylstilbestrol, or chemotherapy, especially use of bevacizumab, thalidomide- or lenalidomide-based combination regimens, particularly those given in combination with high-dose dexamethasone.10 A recent clinical trial of patients with advanced cancer of lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck undergoing chemotherapy (PROTECHT trial) showed a statistically significant (P= 0.02) decrease in thromboembolic events from 3.9% to 2.0% in the groups receiving prophylactic LMWH (such as nadroparin) or placebo, respectively.11 VTE prophylaxis in cancer patients undergoing treatment should be individualized; if prophylaxis is chosen, LMWH (enoxaparin 40 mg/day) or UFH (low dose) should be considered (Table 23.3). Aspirin prophylaxis (81–325 mg daily) is an option for patients receiving thalidomide or lenalidomide for multiple myeloma.10 In chronic lymphocytic leukemia (CLL) patients treated with lenalidomide it was shown that TNFα, C-reactive protein, factor VIII, thrombomodulin, and sVCAM1 were significantly increased from baseline after initiation of treatment (P< 0.001), and TNFα and sVCAM levels were more elevated in patients who subsequently had DVTs, suggesting inflammation and endothelial cell dysfunction played an important role in VTE risk.12 Thus, anti-inflammatory effects of aspirin may contribute to prophylaxis against VTE in addition to antiplatelet effects otherwise not thought to be important for VTE prophylaxis.
Primary Prophylaxis in Immobilized/Hospitalized Cancer Patients
VTE is a fairly common event in hospitalized cancer patients. A retrospective study of over 66,000 hospitalized neutropenic adult cancer patients showed that 3% to 12% of these patients, depending on the type of malignancy, experienced VTE during their first hospitalization.13 Primary prophylaxis is effective in hospitalized medical patients, who undergo a three-fold reduction in VTE when treated with enoxaparin at a daily dose of 40 mg, compared to control patients receiving no treatment. This conclusion is derived from the MEDENOX trial,14 a double-blind randomized study of 1,102 patients with acute medical illnesses who received prophylaxis against VTE (14.9% of these patients had cancer or a history of cancer). Patients were randomized to one of three groups that would receive for 6 to 14 days subcutaneous daily administration of 40 mg of enoxaparin, 20 mg of enoxaparin, or a placebo. The primary outcome was VTE during the ensuing 3 months. The data favored prophylactic treatment with subcutaneous enoxaparin at a dose of 40 mg daily. Adverse events, which included hemorrhage, local reaction, thrombocytopenia, and death from any cause, were not different between the groups receiving enoxaparin and placebo. The weakness of this study was that a more appropriate control group would have received UFH. Therefore, it has been recommended that all hospitalized patients with cancer should receive anticoagulation therapy in the absence of contraindications. A subsequent randomized trial, the LIFENOX Trial, indicates, however, that all-cause mortality is unchanged in medical patients undergoing thromboprophylaxis with LMWH.15 UFH is the agent of choice for thromboprophylaxis in hospitalized patients with a creatinine clearance of < 30 mL/min. A reduced enoxaparin dose of 30 mg daily can also be used in this situation and is preferred if prolonged use is required. Occasional monitoring of anti-factor Xa levels may be appropriate in the setting of renal failure to prevent overdosage and bleeding.
Primary Prophylaxis in Patients with Brain Metastases and Primary Brain Tumors
The risk of VTE in patients with primary or metastatic brain tumors is increased for various reasons including expression of tissue factor16 and PAI-117 by gliomas, immobility due to paresis of limbs affected by the brain tumor or metastasis. Additionally, the use of antiangiogenic agents such as Avastin™ (bevacizumab) may further increase the risk of arterial thrombosis and ironically increase the risk of bleeding.18,19 The challenge in using anticoagulation is balancing the risk of thrombosis with the risk of precipitating intracranial hemorrhage. Studies have shown both increased risk as well as benefit with the use of LMWH prophylaxis in the nonsurgical setting.20
For patients undergoing neurosurgery, the recommended prophylaxis is to initiate LMWH or low-dose UFH 24 hours postoperatively, in combination with mechanical thromboprophylaxis, such as graduated compression stocking and/or intermittent pneumatic compression. This is associated with minimal risk for bleeding.21 Initiation of prophylaxis before neurosurgery in patients with brain tumors may be associated with increased risk for intracranial hemorrhage, as shown in one such study terminated early due to increased bleeding.22
Treatment of Venous Thromboembolism in Patients with Primary Brain Tumors or Brain Metastases
Patients with primary brain tumors or metastases who develop VTE can be treated will full doses of UFH or LMWH.23 Here the use of UFH has the potential advantage over LMWH of a short half-life and the ability to administer protamine to neutralize it in the event of hemorrhage or overdosage. It may be advisable to forego the use of a bolus at the outset of treatment and simply start an infusion and increase the rate with frequent monitoring to prevent inadvertent overdosage. We prefer the use of anti-factor Xa activity monitoring (rather than the aPTT) due to the possibility that the aPTT is not as accurate in its ability to predict anticoagulant effects of heparin. Lupus anticoagulants or increased factor VIII levels may result in spuriously long or short values, respectively. A screening noncontrast head computed tomography (CT) may be considered to exclude recent intracranial bleeding before the initiation of anticoagulation,23 especially in patients with certain types of brain metastases associated with high rates of spontaneous hemorrhage, such as with thyroid cancer, melanoma, renal cell carcinoma, and choriocarcinoma. Evidence of recent spontaneous bleeding is generally considered a contraindication to anticoagulation. IVC filters have a role in this situation, but their placement is often proposed on the mistaken assumption that the patient cannot be anticoagulated, and may be overused.
Treatment of Patients with Trousseau Syndrome
Trousseau syndrome is the constellation of venous and arterial thromboembolic disorders predating or associated with a malignancy.24,25 Patients with this syndrome, even if anticoagulated with warfarin with a therapeutic international normalized ratio (INR), may nevertheless have recurrent thrombi. Other clinical characteristics of Trousseau syndrome include microangiopathy, chronic, low-grade disseminated intravascular coagulation (DIC), and nonbacterial thrombotic endocarditis. UFH, LMWH, and fondaparinux are more effective than warfarin in the treatment of Trousseau syndrome. The dosing of anticoagulation varies depending on the clinical setting. For example, a patient with an acute DVT will require enoxaparin at therapeutic doses, whereas DIC may be controlled with lower doses. Treatment is administered indefinitely (or for as long as tumor persists).
General Approach in Treating Venous Thromboembolism in Cancer Patients
In general, treatment of VTE in patients with cancer consists of acute therapy with LMWH or UFH for at least 5 to 7 days’ duration in patients without contraindications to anticoagulation followed by LMWH or warfarin for at least 3 months. The CLOT trial26 showed an 8% absolute risk reduction without an increase in major bleeding when cancer-related VTE was treated with an LMWH, for example, dalteparin for 6 months compared with warfarin. Chronic therapy with LMWH is associated with superior outcomes in cancer patients with VTE.
Cancer patients with VTE should be treated for a minimum of 3 months, while patients with PE should be treated for at least 6 months, ideally with LMWH. Anticoagulation for an indefinite duration may be considered in patients with active cancer or persistent risk factors who may be bedridden, critically ill, and/or malnourished. Extended anticoagulation therapy with an LMWH may require dosage reduction after an initial period. For example, in the CLOT study, the dalteparin dosing was lowered from 200 units/kg every day to 150 units/kg every day after 1 month.
In the event that warfarin will be used for chronic therapy (due to cost or patient’s preference), there should be a transition phase of at least 5 days during which the acute parenteral anticoagulant (e.g., UFH, LMWH, or fondaparinux) is overlapped with warfarin until an INR of 2.0 or more is achieved. Clinicians should be aware that the warfarin modulation of anticoagulation intensity can be clinically challenging due to drug-drug interactions with commonly used chemotherapeutics, antimicrobials, and other new drugs such as those undergoing testing in Phase I clinical trials.
Most institutions have nomograms for dosing and monitoring of UFH. Anti-factor Xa activity instead of the aPTT has been more frequently used to monitor UFH because of the observation of dissociation between the aPTT and heparin levels measured by anti-factor Xa activity, suggesting heparin resistance. Heparin resistance usually occurs in patients with elevations in factor VIII or von Willebrand factor, antithrombin III (AT) deficiency, increased heparin clearance, elevations in heparin-binding proteins, and use of fibrinogen. Factor VIII, von Willebrand factor, and fibrinogen are acute-phase proteins and elevated factor VIII levels shorten the aPTT.27-29 When UFH is used, the target therapeutic anti-factor Xa level should be 0.3 to 0.7 U/mL.
Anticoagulation Options in Cancer Patients
In patients who develop recurrent VTE despite adequate anticoagulation with warfarin (INR 2.0–3.0) the etiology may be cancer-related hypercoagulability such as the Trousseau syndrome, anatomic causes such as extrinsic vascular compression, and acquired or familial thrombophilia. Treatment can be changed to heparin (LMWH preferred) or fondaparinux. The use of heparin is preferred to use of vitamin K antagonists in the setting of cancer.30 Switching to heparin therapy is an option following failure of fondaparinux to prevent VTE recurrence and vice versa. Twice-daily dosing of enoxaparin is an option for patients exhibiting recurrent VTE while receiving once-daily therapy with am LMWH,31 and escalating the dose of LMWH can be effective for treating cases that are resistant to standard, weight-adjusted doses of LMWH32 If thrombocytopenia occurs during anticoagulation, chemotherapy-induced thrombocytopenia, DIC, heparin-induced thrombocytopenia (HIT), antiphospholipid antibody syndrome (APS), thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura, bone marrow failure, and folate or vitamin B12 deficiency should all be part of the differential diagnosis. Thrombocytopenia does not protect against thrombosis. Anticoagulation therapy should not be withheld because of relative thrombocytopenia alone. The management of antithrombotic therapy in patients with thrombocytopenia requires individualized assessments of the risk of bleeding and the risk of thrombosis.33 Low-dose enoxaparin (< 1 mg/kg/day) may be considered safe at a platelet count in the range of 20 and 55 × 109/L in stem cell transplantation patients who weigh >55 kg.34 On the other hand, thrombocytopenia in APS and HIT may indicate increased disease activity and increased thrombotic potential and aggressive antithrombotic therapy may be warranted.35 Clinical suspicion of HIT should be high when recurrent VTE is observed in a cancer patient receiving or recently exposed to heparinbased therapy. In the typical presentation, platelet counts fall by more than 50% from baseline 5 to 8 days after exposure to heparin. The drop in platelet count can occur even sooner if the patient has been primed by treatment with heparin prior to the current exposure. A major difficulty in diagnosis of HIT is that cancer patients often have multiple reasons for thrombocytopenia, including myelosuppressive drugs, radiation therapy, and infections. An algorithm for calculating pretest probability of HIT includes clinical elements such as presence of thrombocytopenia, timing of drop in platelet count, other causes for thrombocytopenia, and the presence of thrombosis36 and has been modified since its introduction to improve the accuracy of pretest probability estimation.37 Testing for antiplatelet factor 4 antibodies with a sensitive ELISA method can exclude HIT if negative. In cases where the result is positive, the possibility of a false positive can be ruled out by the more specific test for release of 14C serotonin from labeled platelets in the presence of patient serum and heparin. Once the diagnosis of HIT is established, all heparin must be discontinued (even apparently trivial catheter flushes), and an alternative anticoagulant must be started. Alternative anticoagulants that are useful in this setting include direct thrombin inhibitors such as argatroban, bivalirudin, or lepirudin. Long-term anticoagulation with warfarin may be initiated after the platelet count has recovered, and there must be at least 5 days of overlap with the alternative anticoagulant before its discontinuation. If warfarin is initiated while the patient is still in the acute phase of HIT, further acute thrombosis can be precipitated as protein C levels fall upon initiation of warfarin. The highest risk of HIT is seen with use of UFH, and lower risk is seen with LMWH with shorter glucosaminoglycan chains such as enoxaparin. Fondaparinux is manufactured by a total chemical synthesis of the core pentasaccharide chain that is the minimal essential element required for anti-factor Xa anticoagulant activity, and has the least tendency to provoke antiplatelet factor 4 antibodies. Further, it can be used as an alternative to heparin in patients diagnosed with HIT.38
Thrombosis and Venous Access Devices
A majority of cancer patients have, at one time or another, central venous catheters placed for various amounts of time to administer chemotherapy, antibiotics, drugs, or blood products. A frequent complication of long-term central venous catheters is thrombosis that may involve the catheter tip, the entire length of the catheter, or the lumen of the vein in which the catheter resides.39 It would be desirable to prevent such thrombosis not only to preserve central venous access but also to prevent morbidity from obstruction of the large veins of the arm or chest, and to prevent further extension or embolization. Although many strategies for prophylaxis of catheter-related clots have been proposed, a recent Cochrane Database Systematic Review shows that there is no statistically significant effect of prophylactic heparin or low-dose warfarin to prevent catheter-related DVT in patients with cancer.40 Therefore, for cancer patients with indwelling central venous catheters, neither prophylactic doses of LMWH nor “mini-dose” warfarin are recommended to prevent catheter-related thrombosis.
For those patients who have developed a catheter-related DVT, treatment can be initiated with LMWH for 5 to 7 days, followed by warfarin (INR 2–3), or enoxaparin at a dose of 1.5 mg/kg/day for the life-time of the catheter for a total duration of therapy of at least 3 months, (whichever is longer). If the catheter is required but DVT symptoms persist or the clot progresses despite anticoagulation, the catheter should be removed. Thrombolytic therapy with relatively small doses of tPA (one or two treatments of less than 10 mg) has been successfully employed to clear venous occlusions and maintain patency of the vessel without any observed bleeding.41 Patients treated with tPA should have subsequent anticoagulation as above, in the absence of contraindication(s) to prevent repeat thrombosis. In some cases, dilatation of stenotic venous segments may be required when multiple catheters have been inserted and removed for therapy. Low doses of tPA (2 mg) can be used to open clotted catheter lumens.
Indications for Inferior Vena Cava Filters in a Cancer Patient
IVC filters should not be used as a routine method for prevention of pulmonary embolism (PE) in patients with DVT. Rather, their employment should be predicated on genuine contraindications to anticoagulation and/or documented failure of adequate anticoagulation. Patients with baseline cardiac or pulmonary dysfunction severe enough to make any new or recurrent PE life threatening or documented multiple PE and chronic thromboembolic pulmonary hypertension may also be candidates for an IVC filter. Patients with DVT who receive IVC filters are initially protected against PE. However, they are at increased risk for future recurrent DVT as well as future IVC thrombosis or postthrombotic changes in the lower extremities, presumably from increased resistance to venous outflow from the lower extremities. A randomized trial of use of IVC filters compared to non-use of IVC filters for DVT showed that the absolute risk of PE in the first 12 days (symptomatic or not) was reduced from 4.8% to 1.1%, but at 2 years the rate of recurrent DVT was 20.8% in the IVC filter group versus 11.6% in the nonfilter group; there was no difference in mortality between the two groups.42 There are retrievable as well as permanent IVC filters; however, retrievable filters are more prone to migration after placement than permanent filters, and they may, rarely, embolize. If the retrievable filter is not removed within the time frame indicated by the manufacturer, it can become technically difficult to retrieve, and the vascular surgeon or interventional radiologist may recommend that it remain permanently in place.
Results from a recent systemic review of the use of retrievable IVC filters showed that the average retrieval rate was 34%; most filters in fact became permanent devices.43 Serious complications, including strut fracture, with or without embolization or filter migration, vena cava perforation, or vena cava occlusion occur with increasing incidence after prolonged implantation times (> 30 days). In one retrospective series that evaluated 80 patients with retrievable filters placed between 2004 and 2009, a strut fracture rate of 16% was observed, in some cases with embolization of filter components to the heart.44 At the present time, the objective comparison data of different filter designs do not support superiority of any particular design.
PREVENTION, DIAGNOSIS, AND TREATMENT OF VENOUS THROMBOEMBOLISM IN PREGNANCY
Although mortality is rare in pregnant women in developed countries, pregnancy-associated PE remains one of the most frequent causes of the occasional deaths that do occur. Thrombosis during pregnancy and puerperium (the 6-week period following delivery) is attributable to venous stasis in the lower extremities caused by the gravid uterus as well as alterations in hemostasis, such as the progressive increase in fibrin turnover, increased levels of coagulation factors, decreased fibrinolytic activity, and decreased free protein S levels. In addition, the presence of inherited thrombophilias and the APS, as well as a previous history of thrombosis, may accentuate/increase the risk for DVT during pregnancy and the postpartum period.45 Although DVT incidence seems to be evenly distributed throughout the three trimesters, PE is disproportionately found in the puerperium. Poor obstetric outcomes (including preeclampsia, placental abruption, intrauterine growth delay, and fetal loss) may be associated with thrombophilia.46
Diagnosis of Venous Thromboembolism during Pregnancy
In pregnant women, signs and symptoms such as lower extremity edema, back pain, and/or chest pain may be attributed to pregnancy rather than to a possible VTE. Since levels of D-dimer increase during pregnancy, especially during the last trimester, the D-dimer assay may not be helpful in establishing a diagnosis of VTE in pregnant women. Radiologic studies have to be used judiciously, and considered with attention to potential risks to the fetus, and mother, and are usually contraindicated. Compression ultrasonography of the whole leg is preferred as the initial test for suspected DVT or PE in symptomatic patients and does not pose significant risks to the fetus. If the ultrasound is positive for DVT in patients presenting with symptoms suggestive of PE, an indication for anticoagulation is established, the diagnosis of PE is inferred, and no further imaging is required to start treatment.45 If pelvic DVT is a consideration, duplex ultrasonography rather than compression alone will increase sensitivity. If results are equivocal or an iliac vein thrombosis is possible, then magnetic resonance venography should be considered, since it does not carry radiation risks and is reliable, though issues remain, for example, the use of gadolinium and availability of the test. When using ventilation/ perfusion (V/Q) lung scan, the perfusion scan should be completed first and, if normal, PE is excluded, and there is no need for additional radioisotope exposure from the ventilation assessment of the study. If abnormal, a ventilation scan should be performed to confirm mismatch. Those with an indeterminate V/Q scan should have CT pulmonary angiography (CTPA). CTPA is also preferred in the presence of hemodynamic compromise. The fetal radiation exposure, even with current multidetector CT scanning instruments, varies according to trimester of pregnancy, with potentially greater exposure later in gestation if the scanner is programmed to increase the amount of scanner current and radiation to compensate for greater tissue mass.47 It is best to discuss the diagnostic needs of the CT scan with the radiologist so as to minimize fetal radiation through physical measures (shielding), selection of imaging programs appropriate for the pregnant woman at her stage of gestation, and procedural measures (in particular, stopping the study once a diagnosis has been made). The risk to the fetus for developing a later malignancy after a CT imaging procedure has been estimated at one excess cancer per 1,000 abdominal/pelvic CT procedures, which is a small, but not negligible risk.48 In addition to fetal risk, the female breast is radiosensitive and CTPA is associated with an increased lifetime risk of breast cancer of 13.6% with a historic background risk of 1/200.48,49 Reducing radiation to the maternal breast favors use of perfusion scanning,50 and avoiding ventilation scanning when possible.
Management of Pregnant Women at Increased Risk for Venous Thromboembolism
Risk factors for thrombosis include a personal history of VTE, known inherited or acquired thrombophilic mutations/polymorphisms, obesity, advanced maternal age, high parity, and prolonged bedrest. Based on safety data for the fetus, heparin compounds are preferred over warfarin for the prevention and treatment of VTE in pregnancy because UFH and LMWH do not cross the placenta. LMWH is preferred because it has better bioavailability, a longer plasma half-life, a more predictable dose response, and a better safety profile than UFH. The risks of HIT and osteoporosis appear lower with LMWH than with UFH.28,51 Warfarin is generally avoided in pregnant women, due to the risk of teratogenecity when administered between 6 and 12 weeks of gestation. After parturition, either warfarin or heparin anticoagulants can be safely used; since they do not appear in breast milk, they can be given to mothers who are nursing. The prophylactic anticoagulants should be continued for at least 6 weeks postpartum. The therapeutic anticoagulants should be given for a minimum total duration of 6 months.
Tables 23.4 and 23.551 offer guidance on management in defined clinical settings. A complete description of thrombotic conditions, and appropriate treatments during pregnancy as well as during the post partum period, can be found there.
As parturition approaches, women who are receiving LMWH should plan to discontinue treatment 24 hours before delivery. This is particularly important for those in whom epidural or spinal anesthesia is to be used, due to the known additional risk for spinal hematoma that is conferred by use of LMWH. The drug can be resumed 24 hours after delivery. UFH, which has a half-life of 90 minutes, may well be preferable for women who require anticoagulation but whose time of delivery is not predictable.
RECOGNITION OF POSTTHROMBOTIC (“POSTPHLEBITIC”) SYNDROME
Postthrombotic syndrome occurs within 1 to 2 years of an episode of DVT in as many as 20% to 50% of patients.52 In some patients, it may take several months for the initial pain and swelling associated with acute DVT to resolve, so a diagnosis of postthrombotic syndrome should be deferred until after the acute phase has passed. Postthrombotic syndrome results from venous hypertension, which is due to obstruction and damage to the venous valves caused by DVT. The syndrome manifests as chronic pain, tingling, and edema in the affected leg, as well as hyperpigmentation of the skin, and painless ulcers on the medial malleolar surface in the worst cases. The diagnosis is primarily clinical; duplex scanning can be used if the symptoms increase in severity and if surgery is contemplated.
Long-term use of graduated compression stockings (GCS) after symptomatic proximal DVT has been proved to reduce the risk of any postthrombotic syndrome.53 Application of GCS has been recommended to be initiated within 2 to 3 weeks after the first DVT and continued for at least 2 years. However, a recent trial reported that beyond an initial 6-month period use, there was no incremental benefit in prolonging compression therapy for an additional 18 months.54 Although GCS are unlikely to cause harm, they are difficult to apply, uncomfortable, expensive, and require replacement every few months. Based on the current state of evidence on the use of GCS to prevent postthrombotic syndrome, GCS should be applied to patients who have residual leg pain or swelling after proximal or distal DVT, and continued for as long as the patient derives symptomatic benefit or is able to tolerate them.
RECOMMENDATIONS FOR MANAGEMENT OF POSTTHROMBOTIC SYNDROME
For minimally symptomatic postthrombotic syndrome, graduated stockings with moderate compression (15 to 20 mm Hg) or leg elevation at the end of the day may be palliative. An effective way for the patient to reverse or relieve the symptoms of venous hypertension is to elevate both legs above the level of the heart for 30 minutes three or four times daily. During the night, leg elevation can be achieved by elevating the foot of the bed (using blocks placed under the bed if necessary). In the presence of mild to moderate symptoms (edema, aching, heavy legs) graduated stockings with firm compression, 20 to 30 mm Hg, can be used; extra firm is also available (30 to 40 mm Hg) with or without nighttime pneumatic device. Patients who have experienced ulcer formation should wear stockings daily throughout the day. Nonelastic stockings that are comprised of multiple layers attached by Velcro (CircAid™) can also be used and may be easier to apply. Intermittent pneumatic compression in combination with sustained graduated compression has demonstrated improved outcome in patients with venous leg ulcers.55
Pharmacologic Approach to Postthrombotic Syndrome
Horse chestnut seed extract, such as aescin was found to be effective for short-term treatment of chronic venous insufficiency symptoms such as leg pain and edema compared to a placebo. A short-term (up to 3 weeks) trial of twice-daily horse chestnut seed extract (available at natural product stores) may be suggested to patients whose postthrombotic symptoms are not adequately controlled by GCS. However, larger and more rigorous trials are needed to assess its long-term effectiveness and safety.56 In patients with venous leg ulcers, pentoxifylline and rutosides are recommended in addition to local care and compression and/or intermittent pneumatic compression by ACCP guidelines.57
Table 23.6 Approaches to Prevent and Treat Postthrombotic Syndrome
Prevention
Management
DVT, deep venous thrombosis; PTS, postthrombotic syndrome.
Adapted from Kahn SR.The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Program. 2010:216-220.
There is no evidence that diuretics are effective for the treatment of postthrombotic-related edema, or that nonsteroidal anti-inflammatory drugs improve symptoms of postthrombotic syndrome beyond their analgesic effects.
Surgical Management of Postthrombotic Syndrome
Surgical correction of superficial venous reflux in addition to compression bandaging was not shown to improve ulcer healing but did reduce recurrent ulceration compared with compression therapy alone in a randomized trial.58 The available strategies to prevent and treat postthrombotic syndrome is summarized in Table 23.6.59
ANTIPHOSPHOLIPID SYNDROME
APS is an acquired thrombophilic condition characterized by arterial or venous thrombosis or pregnancy morbidity in patients with persistent positive lupus anticoagulants (LAs), anticardiolipin antibodies, or anti-beta-2 glycoprotein I for at least 12 weeks apart. Antiphospholipid antibodies (APA) promote activation of endothelial cells, monocytes, and platelets, and overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenic role. Of the different APA, the LA is the strongest predictor of thrombotic outcomes related to APS.60
Prevention of thrombosis is a major goal in patients with APA. The 13th International Congress on APA recommended that all APA carriers receive primary thromboprophylaxis with usual doses of LMWH in high-risk situations, such as surgery, prolonged immobilization and puerperium, and indefinite anticoagulation at an INR of 2.0 to 3.0 for patients with APS presenting with first venous events (secondary thromboprophylaxis). APS patients with arterial disease or recurrent events, or both, may need a more aggressive treatment, such as warfarin with a target INR of more than 3.0 or combined antithrombotic therapy with aspirin or other antiplatelet medications. In cases of first venous event, patients with a single positive test for APA (anticardiolipin or anti-β2-glycoprotein 1), and a known transient precipitating factor, anticoagulation could be limited to 3–6 months. In patients with difficult management due to recurrent thrombosis, fluctuating INR levels, major bleeding or a high risk for major bleeding, alternative therapies could include long-term LMWH, hydroxychloroquine, or statins.60,61
NEW ANTICOAGULANTS
Warfarin therapy is affected by changes in diet and interactions with other drugs, requiring ongoing laboratory monitoring. Further, the onset of action is delayed, and the full anticoagulant effect may not be achieved for several days, necessitating concomitant use of parenteral anticoagulants with rapid onset of action (e.g., LMWH) while the dose is titrated. These limitations stimulated the search for alternative oral anticoagulants. The new oral direct thrombin inhibitor (dabigatran) and oral factor Xa inhibitors (apixaban and rivaroxaban) have good bioavailability and reliable anticoagulant activity, and are promising new medications. In 2010, the FDA approved dabigatran (Pradaxa™) 150 mg twice daily for the reduction of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Approval was based on a multicenter, active-control trial, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), in which 18,113 patients were randomly assigned to receive 150 mg of dabigatran, 110 mg of dabigatran, or warfarin.62 Dabigatran was given twice daily; warfarin was titrated to a target INR of 2.0 to 3.0. Both dabigatran regimens were noninferior to warfarin, but the 150-mg regimen was significantly superior to warfarin and to the 110-mg dabigatran regimen. Both regimens have been considered safe and effective if studied alone in comparison with warfarin, although the noninferiority finding for the 110-mg dose was less compelling, and only the 150-mg daily-dosing regimen was approved by the FDA.63 Although it is not approved for treatment of DVT in the Unites States, a Phase III trial (RE-COVER) comparing 150 mg dabigatran BID with standard warfarin showed noninferiority of dabigatran to warfarin.64 Likewise, trials of for prophylaxis of VTE in the setting of total hip65 or total knee replacement66,67 have shown noninferiority of dabigatran to warfarin for this indication.
In 2011, the FDA approved rivaroxaban (Xarelto™) 10 mg once daily for 35 days following hip replacement and for 12 days following knee replacement for prevention of DVT in patients undergoing joint replacement surgery. The approval is based on testing of rivaroxaban’s safety and efficacy in the four Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) trials.68-71 The data from the RECORD trials showed significantly greater efficacy of rivaroxaban, both in head-to-head comparison with enoxaparin and when comparing extended-duration (5 weeks) of rivaroxaban with short-duration enoxaparin (2 weeks), followed by a placebo. In these trials, rivaroxaban and enoxaparin demonstrated similar safety profiles, including low rates of major bleeding. Also in 2011, the FDA approved rivaroxaban 20 mg once daily to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. Supportive evidence came primarily from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in which 14,264 patients were randomly assigned in a double-blind fashion to either 20 mg of rivaroxaban once daily or warfarin therapy targeting an INR of 2.0 to 3.0. In this study, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. 72 In 2012 the FDA approved the use of rivaroxaban for treatment of DVT or PE based on the results of the EINSTEIN73 and EINSTEIN-PE74 trials, respectively, which showed rivaroxaban to be non-inferior to standard therapy with enoxaparin/warfarin.
The other oral factor Xa inhibitor, apixaban is also under FDA consideration for the prevention of stroke in subjects with atrial fibrillation. In the Apixaban for reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban at a dose of 5 mg twice daily was compared with warfarin (target INR 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. Apixaban was found to be superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with atrial fibrillation.75Anticoagulant medications with novel mechanisms or important features that promise advantages over our current armamentarium are reviewed in Ref. 66. and Ref. 77.
Certain disadvantages remain for all of the new oral anticoagulant medications that are in advanced stages of clinical testing. There currently are no reliable ways to reverse or neutralize these medications in the event of overdose or bleeding, in contrast to warfarin, for which reversal with vitamin K or fresh frozen plasma is readily accomplished. The rapid onset of anticoagulation, a benefit for most applications, is matched by an equally rapid decrease in the anticoagulant effect in contrast to the gradual onset/slow decrease of effect seen for warfarin. A quick onset of action may be problematic when a patient is poorly compliant and frequently misses doses of a drug that disappear rapidly from the circulation, particularly under conditions of high thrombotic risk. Although laboratory testing for anticoagulant effects can be accomplished by use of the ecarin clotting time, for instance, in the case of the direct antithrombin drugs, these are not as yet commonly available in contrast to the prothrombin time and INR. These drugs are all significantly more expensive than generic warfarin, and none are as yet given FDA approval for treatment of VTE (secondary prophylaxis), and a place for warfarin will likely remain even after FDA approval, in patients whose warfarin dose is stable and are not difficult to manage, or who cannot afford the more expensive novel agents.
These concerns aside, a new era of easier-to-use oral anticoagulants for the prevention and treatment of VTE is now beginning, which is a welcome development.
References