Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 20
Venous thromboembolism in neurologic disease MICHAEL J. SCHNECK* Departments of Neurology and Neurosurgery, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
INTRODUCTION Patients with systemic venous thromboembolism (VTE) can present with superficial venous thrombosis (SVT), deep venous thrombosis (DVT), or pulmonary embolism (PE). Both SVT and DVT may occur as partial or total occlusions of draining veins of the upper or lower extremities. SVT and DVT are of concern because of the potential risk of thrombophlebitis and propagation of emboli to the pulmonary circulation. PE is of concern because occlusion of the pulmonary vessels can lead to hypoxia, right heart strain, and death. The risk of PE is far greater from DVT than from SVT. As many as 10–25% of patients with DVT will die from subsequent PE (Danish et al., 2004). Without treatment, PE will lead to significant morbidity and mortality, with a 7 day mortality as high as 75% (Geerts et al., 2008). Patients with neurologic disease, or those undergoing procedures for a neurologic or neurosurgical condition, have a very significant VTE risk. Thus, awareness of this risk is critical to prevent the subsequent complications related to VTE.
EPIDEMIOLOGY (WITH SPECIFIC FOCUS ON NEUROLOGIC DISEASE) About 600 000 patients develop a new DVT each year in the US (Browd et al., 2004; Danish et al., 2004; Geerts et al., 2008). One third of these patients are diagnosed with an isolated lower extremity DVT and these DVTs are the primary etiology leading to PE (Browd et al., 2004; Geerts et al., 2008). In the US, the annual PE rate is 1–2 per 1000 persons with an estimated attributable case-fatality rate of 200 000 hospitalized patients (Kearon et al., 2008). Almost 25% of all patients with
PE die suddenly, and the survival rate of the remainder is only 71% (Heit et al., 1999). Presumed asymptomatic DVT is not “benign,” with an estimated rate of fatal PE from these DVT ranging from 13% to 15% (Giannoukas et al., 1995; Heit et al., 1999). While calfvein thrombosis, compared with above the knee thrombosis, has a lower case-fatality rate, it has a 40–50% risk of extension into proximal leg veins (Geerts et al., 2008; Decousus et al., 2010; Lautz et al., 2010). Of note, an 844 patient series with below the knee venous thrombosis found that 24.9% had concomitant DVT or PE (Lautz et al., 2010). Additionally, of 600 patients with isolated SVT, 10.2% developed thromboembolic complications at 3 months, though 90.5% had been treated with anticoagulants (Decousus et al., 2010). Upper extremity DVT is also a significant, albeit less known source, with case rates upwards of 13.5%, mainly attributable to peripherally inserted central catheters and central venous lines. While upper extremity DVT is less common than lower extremity DVT, the risk of PE is high, at 36%, for all upper extremity DVT (Hingorani et al., 1997). There are a number of risk factors for VTE, as listed in Table 20.1. Population risk factors for first-ever VTE in the Copenhagen City Heart Study included obesity, cigarette use, male sex, socioeconomic status, and diastolic arterial blood pressure greater than 100 mmHg (Holst et al., 2010). Hereditary and acquired thrombophilias include activated protein C resistance, factor V Leiden mutation, prothrombin G20210A mutation, antiphospholipid antibodies, lupus anticoagulant, elevated factor VIII levels, protein C or protein S deficiency, hyperhomocysteinemia, dysfibrinogenemia, antithrombin deficiency, and heparin-induced thrombocytopenia (Rees et al., 1995; Rosendaal et al., 1995, 1998; Wahl et al., 1998; Runchey
*Correspondence to: Michael J. Schneck, M.D., Professor of Neurology and Neurosurgery, Loyola University Chicago, Stritch School of Medicine, Maguire Building, Suite 2700, 2160 South First Avenue, Maywood, Illinois 60153, USA. Tel: þ1-708-216-2662, Fax: þ1-708-216-5617, E-mail: [email protected]
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Table 20.1 Risk factors for deep vein thrombosis or pulmonary embolism Inherited and acquired thrombophilias Surgery (most commonly lower extremity orthopedic and pelvic surgeries) Indwelling central venous catheters and peripherally inserted central catheter lines Major trauma Prolonged paralysis Age >60 years old Oral contraceptive use Hormone replacement use Malignancies Chemotherapy use Heart disease Ischemic or hemorrhagic stroke Nephrotic syndrome Prior history of venous thromboembolism Family history of venous thromboembolism
et al., 2002; Browd et al., 2004; Lijfering et al., 2010). The leading cause of acquired (as opposed to hereditary) thrombophilias is the antiphospholipid (APL) syndrome. The risk of venous thrombosis is higher with the APL syndrome in the presence of a concomitant lupus anticoagulant. The VTE risk associated with hereditary, acquired, or mixed thrombophilia of is not clear, but factor V Leiden and prothrombin G20210A mutations are among the thrombophilic markers for which there is a very strong association (Rees et al., 1995; Rosendaal et al., 1995, 1998; Lijfering et al., 2010). The factor V Leiden mutation is the most common prothrombotic mutation in Caucasians but is very rare in Asians and African Americans (Rees et al., 1995; Lijfering et al., 2010). The prevalence of factor V Leiden mutation is approximately 5%, and that of the prothrombin G20210A mutation is approximately 2% in white patients. Heterozygous patients with factor V Leiden mutations have a fivefold to sevenfold increased VTE risk, whereas heterozygous prothrombin G20210A carriers have a threefold to fourfold higher VTE risk. Double heterozygous carriers of factor V Leiden and the prothrombin G20210A mutation have a 20-fold increased risk of first-ever VTE, and homozygous factor V Leiden carriers have an 80-fold increased VTE risk. Heterozygous carriers of each mutation alone do not have an increased risk compared to noncarriers (Lijfering et al., 2010). Hospitalized patients are at particular risk for VTE which has been deemed to be one of the most preventable causes of inpatient mortality. The American College of Chest Physicians (ACCP) 2008 guidelines estimate a
hospital prevalence of VTE ranging from 10% to 40% in moderate-risk patients and a prevalence as high as 80% among high-risk patients (Geerts et al., 2008). Neurologic and neurosurgical disease is highly associated with an increased VTE risk in hospitalized patients. Neurologic impairments are present in about 7% of all immobile inpatients at risk for VTE (Gaber, 2007). DVTs may be present in 15–40% of all hospitalized neurosurgical patients, 40–80% of all patients with major head trauma, and 20–40% of all hospitalized stroke patients. Patients with spinal cord injury, not treated with prophylactic anticoagulation, have a particularly high DVT rate of approximately 60–80% (Browd et al., 2004). Patients with head injury have a reported DVT rate as high as 31.6%, though the DVT rate is lower, at 25.5%, among patients with isolated head injuries (Rogers et al., 2002; Sharma et al., 2007). Older age, subarachnoid hemorrhage, associated lower extremity injury, and higher injury severity scores have been associated with increased risk in patients with moderate to severe brain injury (Sharma et al., 2007). These patients with traumatic injuries and a high DVT rate are also at particularly high risk for PE because patients with head trauma also have relative contraindication to pharmacologic prophylactic anticoagulation (Rogers et al., 2002; Sharma et al., 2007). The overall incidence of DVT in neurosurgical patients is highly variable but may be as high as 50% (Auguste et al., 2004; Browd et al., 2004). The incidence of PE ranges from 1.5% to 5%, with a 9–50% related risk of death (Auguste et al., 2004; Browd et al., 2004). In elective neurosurgical and spine procedures, the risk of DVT is much lower, particularly if patients receive pharmacologic prophylaxis (Sansone et al., 2010). In Japan, the risk of symptomatic VTE in neurosurgical patients is only 0.07–0.22%, but in one small 37 patient series, the lower extremity DVT rate was 13.5% with 60% of those five DVT patients having an asymptomatic PE (Taniguchi et al., 2009). Thus, ascertainment bias remains a problem in determining the true rate of VTE in neurosurgical patients. VTE risk factors in neurosurgical patients include concomitant hemorrhagic or ischemic stroke, spinal cord injury, benign or malignant CNS tumors, the duration of the surgical procedure, and the general duration of hospital immobility (Hamilton et al., 1994; Rogers et al., 2002; Browd et al., 2004; Danish et al., 2004; Sharma et al., 2007; Ageno et al., 2009; Carlile et al., 2010; Ekeh et al., 2010). For spine surgery, the type of case may reflect the underlying VTE risk. A large series of 108 419 cases from the Scoliosis Research Society morbidity and mortality database, reported the 2004–2007 complication rates related to clinically evident VTE for lumbar microdiscectomy, anterior cervical discectomy and fusion, and lumbar
VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE 291 spinal stenosis decompression. The rate of the DVT rate histologic grade 4 tumor, and prolonged surgery (longer was 1.18/1000 and the PE rate was 1.38/1000 cases with a than 4 hours). Mortality is also higher for astrocytoma mortality rate of 0.34/100 cases. The rates were lowest patients with VTE, with a 30% increased risk of death for lumbar microdiscectomy, and highest for spine prowithin 2 years (Browd et al., 2004). The risk of VTE is cedures for metastatic tumors (Smith et al., 2010). The lower in other tumor types but is not insignificant. risk of PE may also be higher in patients undergoing VTE has been recognized as one of the more common combined anterior and posterior surgeries as compared complications in patients with meningiomas though the with posterior spine surgery only (Ozturk et al., 2010). rate is relatively low for this tumor type. Sughrue Overall, the VTE rate in neurosurgical patients is not et al. (2011) reported a series of 834 patients who underhigh. A meta-analysis of patients undergoing elective went craniotomy for meningioma in which 57 (6.8%) had neurosurgical procedures noted that the DVT rate was serious medical complications with a reported clinically just 1.09% and the PE rate was 0.06% ( Sansone et al., symptomatic VTE rate of 0.8% (7/834). 2010). For neurosurgical patients with cancer, however, Stroke patients are also at very high risk for VTE. the VTE rates are much higher. In general, cancer conTong et al. (2010) reported that the prevalence rate of veys upon all patients a particularly significant VTE risk, DVT was 0.8% and the rate of PE was 0.3% for all but patients with central nervous system (CNS) tumors patients hospitalized with ischemic stroke as a primary are at particularly high risk (Hamilton et al., 1994; diagnosis. Medical complications were associated with Semrad et al., 2007). Patients with an intracranial tumor, an increased hospital length of stay in this cohort. Over in an Australian series of 2279 patients treated only with the period from 1998 to 2007, the overall length of stay of sequential compression devices (SCDs), had a higher hospitalized stroke patients declined but remained VTE rate than patients with spinal cord tumors. While unchanged for those patients with medical complicathe overall rate in this series was low; there was a roughly tions (including DVT or PE, stroke-related myocardial 3% VTE rate among the patients with intracranial tumors infarction, or pneumonia). Early stroke-related DVT (Smith et al., 2004). Cumulative rates of symptomatic was studied in a series of 278 ischemic and 12 hemorVTE as high as 30% may occur in patients with brain rhagic stroke patients who underwent venous duplex tumors (Perry et al., 2010). It is hypothesized that ultrasonography (VDU) on day 3 and day 9 (Bembenek tumor-induced hypercoaguable states may be present et al., 2011). DVT occurred in 8% of these stroke patients in patients with malignant astrocytoma, especially in with 83% (24/29) of DVTs occurring at day 3. A subsethe context of higher grade tumors. This VTE risk in quent 3% (9/299) had new onset DVT at day 9. These patients with astrocytoma is attributed to specific coagnewly discovered DVTs increased the risk of 3 month ulation abnormalities, including elevated fibrinopeptide mortality with an odds ration (OR) of 12.4 (95% CI A, elevated fibrinogen fragment Bb 15-32, and 1.72–89.4). Adjusted for stroke severity and prestroke decreased activated partial thromboplastin times with disability, an elevated serum C-reactive protein (CRP) resultant increases in procoagulant activity and platelet was associated with increased risk of DVT (OR 8.75; activation (Hamilton et al., 1994). The astrocytoma95% CI 1.61–47.6) (Bembenek et al., 2011). The risk is associated VTE rate depends upon a number of factors related both to immobility and to a greater risk for hyperincluding ascertainment biases related to the diagnosis coagulable states in patients with stroke. Patients with and associated prophylaxis regimens. Among 9489 cases cryptogenic stroke or transient ischemic attack (TIA) of hospitalized patients with malignant glioma hospitalmay also have a greater risk of silent PE. Patients who ized during a 6 year period in California, the cumulative had a patent foramen ovale (PFO) and underwent V/Q 2 year incidence of VTE was 7.5% with 55% being diagscans were identified from a stroke registry. The evalunosed within 2 months of surgery. Risk factors included ation included 151 patients from the 266 patient registry. histology of glioblastoma multiforme (GBM), older age, In 35% of the patients, a silent PE was found (56/151), and three or more chronic associated medical conditions. though a DVT was identified in only 7% (11/151) of the The presence of VTE conveyed a greater risk of death patients. An atrial septal aneurysm was independently within 2 years (HR 1.3 95% CI 1.2–1.4) (Semrad et al., associated with PE. There was also an association with 2007). VTE rates in the 6 weeks after surgery range from oral contraceptive use and PE among the women in this 3% to 60% (Semrad et al., 2007). Beyond this 6 week series of PFO-related stroke (Tanislav et al., 2011). postoperative period, the VTE rate remains high in astroIn stroke patients, clinical prediction models based on cytoma patients, with symptomatic DVT rates of 24% clinical factors alone were unable to identify immobile reported over the 17 months following initial surgery stroke patients at low versus high risk for DVT (Semrad et al., 2007). Patients with astrocytoma and (Dennis et al., 2011). DVT is a clinically significant comthe following risk factors have a higher VTE risk: age plication in these patients, however. Approximately 75% older than 60 years, larger tumor size, chemotherapy, of patients may develop DVT without prophylaxis
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(Kelly et al., 2001; Adams et al., 2007; Sherman et al., 2007; Kase et al., 2009). PE is also a significant cause of mortality in stroke patients, with upward of 25% of early poststroke deaths attributable to PE (Kase et al., 2009). Most fatal PE occurs within 2–4 weeks after an ischemic stroke. The diagnosis of PE can be challenging in stroke patients who have accompanying cognitive deficits, dysphagia, or speech impairments, and concomitant pneumonia or fever. A high index of clinical suspicion is particularly needed in stroke patients (Kumar et al., 2010). Patients with hemorrhagic stroke have a VTE rate that is roughly 65% higher than patients with ischemic stroke (Skaf et al., 2005). In a single center retrospective series of patients treated for aneurysmal subarachnoid hemorrhage (SAH), the incidence of asymptomatic DVT was 24% in patients who had surveillance screening by VDU. Risks for DVT were higher with greater Hunt and Hess aneurysmal SAH scores, length of ICU stay, and total length of hospital stay (Ray et al., 2009). Patients with neuromuscular and neurodegenerative diseases also have a high VTE risk particularly because of immobility but also because patients with autoimmune states have a greater risk for hypercoagulability (Ageno et al., 2009). The actual incidence in many of these neurologic diseases is not well studied (Ageno et al., 2009). VTE risk was elevated in a number of autoimmune diseases (Ramagopalan et al., 2011). Among them were multiple sclerosis, myasthenia gravis, and dermatomyositis or polymyositis. For multiple sclerosis, the rate ratio ranged from 2.14 to 2.52 in the cohorts studied. For myasthenia gravis, the rate ratio ranged from 2.04 to 2.34. For dermatomyositis or polymyositis, the rate ratio ranged from 1.98 to 3.04. By comparison, the highest rates in this study were seen for systemic lupus erythematosus (rate ratios of 3.61–4.60) and polyarteritis nodosa (rate ratios of 2.88–5.36). Multiple sclerosis patients who are at particular risk for DVT are those who are bedridden or wheelchair bound. In one series of 132 patients, the average duration of illness was 18.7 years and only 25 patients were able to walk with even some assistance. A total of 113/132 patients had lower limb edema. All of these 132 patients had VDU and a DVT was found in 58 patients (43.9%). A total of 32 had a prior history of DVT. D-dimer levels were elevated in 45% (26/58) of patients with DVT and 35% (26/ 74) of patients without DVT. Of note, a number of multiple sclerosis patients had elevated D-dimer with VDU negative DVT. The converse was also true. Thus, D-dimer values may be of limited utility in excluding VTE in multiple sclerosis patients (Arpaia et al., 2010) For Parkinson disease, in a study of 81 patients, the asymptomatic DVT rate, determined by VDU, was 4.9 % (Burbridge et al., 1999). In a Mayo Clinic study
of the morbidity associated with 114 Guillain–Barre´ patients admitted to an intensive care unit, the incidence of DVT was 4%, and the incidence of PE was 3%. The exact details are unknown but the authors suggested that most, if not all, of the patients were on some form of pharmacologic prophylaxis. (Henderson et al., 2003). A retrospective study of 73 patients with Guillain–Barre´ syndrome reported an incidence of symptomatic DVT of 7% (five patients with DVT; three of whom also had PE) (Gaber et al., 2002). Fifty of the 73 patients were on pharmacologic prophylaxis. Of the five patients with DVTs, two were not anticoagulated and the other three were on enoxaparin. Finally, patients who receive intravenous immunoglobulin (IVIG) treatment for neurologic diseases are also at increased risk for thromboembolism complications including VTE (Hommes et al., 2004; Vucic et al., 2004)
GENERAL PRINCIPLES Presentation and diagnosis Frequently, patients with VTE will not have apparent clinical symptoms or have symptoms or signs that can be indistinguishable from other disease states. Thus, for example, extremity swelling due to DVT may be attributed to dependent edema due to paralysis, and pain and burning due to DVT may be attributed to neuropathy in some patients. The classic symptom onset of a DVT is that of an acute painful, enlarged, swollen, and erythematous extremity, but some 50–60% of patients will not have clinical symptoms (Danish et al., 2004). Additionally, a Homan’s sign may be present, but the accuracy of the Homan’s sign is very unreliable with both low sensitivity and specificity. Estimates are that this sign is present in only 33% of patients with DVT, with an accuracy ranging from 8% to 50% for patients with DVT (Urbano, 2001). Similar to DVT, almost 50% of patients with PE have no apparent clinical symptoms. In those instances, PE is typically found in the context of an initial DVT diagnosis (Geerts et al., 2008). The classic symptom presentation of PE includes pleuritic chest pain, variable degrees of shortness of breath, and cardiac dysrhythmias or sinus tachycardia. The signs and symptoms may help to assess pretest probability for PE but are not sufficiently accurate for the exclusion of PE. In these circumstances, arterial blood gases and electrocardiogram may be suggestive but are also not sufficiently accurate to exclude PE. Echocardiography may further hint at a possible PE if there are signs of increased pulmonary arterial pressures such as right heart strain (McConnell’s sign) though this is not a specific sign for PE (Torbicki, 2005). Elevated D-dimers are found in most patients with VTE but may also be present in patients with acute
VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE stroke, myocardial infarction, malignancy, or autoimmune states; patients undergoing recent surgery; or patients with recent history of trauma. Thus the utility of a negative D-dimer serum assay is to further exclude patients at low or intermediate probability for VTE in the outpatient setting (Wells et al., 2003; Thachil et al., 2010). While a positive D-dimer is not diagnostic, a negative D-dimer has a negative predictive value of 99% (Wells et al., 2003). The D-dimer assay is much less useful in the diagnosis of VTE in hospitalized patients where false-positive tests are common (Thachil et al., 2010). Ultimately, the diagnosis of DVT or PE is dependent on confirmatory imaging tests. Contrast venography is the nominal gold standard for the diagnosis but is rarely used because of limited availability, cost, patient discomfort, and a significant risk of contrast-induced thrombosis (Browd et al., 2004; Miller and Lee, 2005). Impedance plethysmography is also rarely used as it does not help to identify nonocclusive thrombus and cannot easily find calf-vein thrombosis. Thus, the mainstay for DVT diagnosis and screening is venous duplex ultrasonography (VDU) (Taniguchi et al., 2009). VDU is a readily available tool that is 89–96% sensitive and 96–100% specific in the diagnosis of significant DVT. VDU has a lower sensitivity (75%) for isolated calf DVT (Browd et al., 2004; Giannoukas, et al., 1995; Stein et al., 2010). In addition to widespread availability at most hospitals, VDU is relatively less expensive, portable, and noninvasive. It can therefore be used in a wide variety of settings including the intensive care unit, emergency department, and ambulatory clinics. Limitations of VDU include dependence on operator skill and problems in visualizing the veins in certain patients. VDU also cannot adequately visualize iliac or pelvic veins. The use of VDU, along with clinical prediction rules, improves the DVT likelihood ratio with a specificity of 98–100% to 0.2 among low-risk patients, 1.3 among moderate-risk patients, and 3.3 among highrisk patients (Thachil et al., 2010). In this regard, MR venous imaging has a distinct advantage compared to VDU for imaging the iliac and other pelvic veins and is also more accurate for imaging of below the knee DVT. When compared to conventional venography, MR imaging has an estimated sensitivity of 91.5% and specificity of 94.8% in pooled estimates for detection of lower extremity DVT. The sensitivity is higher for proximal DVT as opposed to distal DVT (Sampson et al., 2007). MR imaging is still superior to CT venography or VDU. Using MR imaging as the reference standard, VDU has a sensitivity of 93.5% and specificity of 98.0%, and CT venography has a sensitivity of 89–100% and specificity of 94–100% (Sampson et al., 2007; Miller and Lee, 2005). The limitations of MR venography are cost and limited availability.
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Pulmonary angiography is the “gold standard” for the diagnosis of PE. Ventilation/perfusion (V/Q) scans and spiral or helical CT angiography are less invasive and so these are the preferred modalities (PIOPED Investigators, 1990; Coche et al., 2001). The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study demonstrated that a normal V/Q scan excluded PE with high sensitivity and specificity. (PIOPED Investigators, 1990) In this study, a high probability V/Q scan had a 95% positive predictive value for those patients where there was a strong clinical suspicion for PE. In 40–70% of patients, however, a low or intermediate probability V/Q scan result occurred and so V/Q scans were nondiagnostic for exclusion of PE in many patients where there was an intermediate or high pretest PE probability (Kearon et al., 2008). In these patients, further testing that includes DVT screening and/or pulmonary angiography is indicated if there is a sufficiently high suspicion for PE. Unfortunately, high probability V/ Q scan results occur in only 41% of patients with angiographically proven PE, and a negative lower extremity ultrasound occurs in 40% of angiographically proven PE. Conversely, a negative D-dimer assay and a negative lower extremity duplex ultrasound are associated with a negative predictive value of greater than 99% in making a negative diagnosis of PE (Coche et al., 2001; Thachil et al., 2010). Spiral CT is probably superior to V/Q scans for detection of PE. V/Q scans, however, have an advantage in patients who do not have reasonable kidney function or who have contrast dye allergy, for whom spiral CT is therefore contraindicated (Coche et al., 2001). On CT, a pulmonary artery occlusion appears as either a partial or complete filling defect (Fig. 20.1). Spiral CT has a sensitivity of 99% and a specificity of 95% compared to the gold standard of pulmonary angiography (Coche et al., 2001). MR angiography (MRA) of the pulmonary vessels is also an option but is not superior to spiral CT (Stein et al., 2010). The Wells criteria are a useful clinical prediction tool for identifying patients at high risk for VTE. Separate prediction tools exist for DVT and PE (Wells et al., 1997, 2001; Thachil et al., 2010). Among the risk factors incorporated into the DVT prediction tool are: active cancer, asymmetric pitting edema, swelling of the entire leg, asymmetric calf swelling, presence of nonvaricose superficial veins, paralysis or leg immobilization, bedridden > 3 days, history of major surgery in the prior 4 weeks, localized tenderness along the deep venous distribution, and presence of nonvaricose collateral superficial veins. Risk factors incorporated in the Wells predictive criteria for PE without diagnostic imaging include: active cancer, clinical signs of DVT, hemoptysis, tachycardia, immobilization including paresis or
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Fig. 20.1. A 73-year-old woman with a longstanding history of tinnitus and right hearing loss of undetermined etiology had a syncopal episode. At an outside hospital a CT scan revealed a large right cerebellopontine angle mass. On admission, she underwent an echocardiogram for evaluation of the syncope. This echocardiogram showed a hypokinetic right ventricle with decreased contractility sparing the apex (McConnell’s sign). A spiral CT of the pulmonary vessels (coronal cut below) was then obtained. This revealed filling defects with the appearance of pulmonary emboli noted bilaterally in both pulmonary arteries branching into several segmental arteries consistent with multiple pulmonary emboli. There was also mild dilatation of the right pulmonary artery.
leg paralysis, bedridden > 3 days, history of major surgery in the prior 4 weeks, prior DVT or PE, and an alternative diagnosis that is less likely than PE. Additional clinical and historical risk factors conveying particular high risk of DVT or PE include: age 75 years or older, acute spinal cord injury with paralysis, elective major lower extremity surgeries, leg, hip or pelvis fractures, prior history of stroke or trauma, and prior history of VTE (Bahl et al., 2010). Increased risk associated with thrombophilia history or markers were: a history of congenital or acquired thrombophilias, a family history of thrombosis, presence of prothrombin G20210A, factor V Leiden mutations, elevated homocysteine levels and acquired thrombophilias including a positive lupus anticoagulant, and elevated anticardiolipin antibodies.
General treatment issues PROPHYLAXIS Mechanical and/or pharmacologic thromboprophylaxis clearly decreases the incidence of VTE, and all-cause mortality, in hospitalized patients. There are defined advantages and disadvantages for both mechanical
and pharmacologic prophylaxis. Additionally, there may be risk/benefit profile differences between the various pharmacologic agents used for VTE prophylaxis, particularly related to the risk of hemorrhagic complications. This risk of hemorrhagic complications is particularly problematic in patients with neurologic or neurosurgical disease, and the guidelines for VTE prophylaxis established in the general medical and surgical population may not be easily extended to the neurologic patient population (Geerts et al., 2008). VTE prophylaxis entails mechanical prophylaxis, pharmacologic prophylaxis or a combination of both modalities. Mechanical prophylaxis that is achieved by early ambulation, intermittent pneumatic compression (IPC), or sequential compression devices (SCD), has been shown to decrease the risk of DVT (Agnelli et al., 1998; Rogers et al., 2002; Geerts et al., 2008; Kearon et al., 2008; Taniguchi et al., 2009; CLOTS II Investigators 2010; Morris and Woodcock, 2010; Sachdeva et al., 2010). The utility of graduated compression stockings has been debated. A Cochrane metaanalysis of 18 studies suggested that the use of graduated elastic compression stockings was of benefit when used with additional prophylactic therapies (Sachdeva et al., 2010). The CLOTS II (Clots in Legs Or sTockings after Stroke) trials (CLOTS Investigators, 2010) suggested that thigh-length stockings were more effective than below-the-knee stockings in patients with stroke screened by VDU at 7–10 days and 15–20 days posthospitalization. The CLOTS II study reported a proximal DVT rate of 6.3% for thigh-length stockings and 8.8% for below-the-knee stockings. However, skin breakdown occurred in 3.9% of those with thigh-length stockings and in only 2.9% of those with below-the-knee stockings. A caveat of the CLOTS II study was that the results of the CLOTS Trial I of thigh-length stockings versus placebo were not associated with a clinically significant reduction in proximal DVT but were associated with significant skin breakdown events (Dennis et al., 2009). Compression devices (either intermittent pneumatic compression (IPC) or sequential compression devices (SCDs)), may be used with or without elastic stockings. These devices are assumed to prevent DVT by promoting hemodynamic flow and fibrinolytic function. These devices are associated with low risk, though there is a concern that thrombus may be dislodged by an SCD in patients with have undetected or pre-existing extremity thrombus. A systematic review suggested that IPC/ SCD may be associated with a decrease in the rate of DVT but the evidence is weak (Agnelli et al., 1998; Rogers et al., 2002; Kearon et al., 2008; Morris and Woodcock, 2010). The main advantage of mechanical prophylaxis is a reduced risk of bleeding. These devices, however, are still associated with a high rate of DVT.
VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE Among neurosurgical patients treated with SCDs, the DVT rate is as high as 32% (Taniguchi et al., 2009). By contrast, the rate of DVT using pharmacologic prophylaxis in a similar population is much lower. Even with the use of pneumatic compression devices, the incidence of DVT is high with reported rates of 32% in neurosurgical patients. Pharmacologic thromboprophylaxis, however, is associated with a reduction of DVT incidence by up to 50% (Agnelli et al., 1998; Geerts et al., 2008). Pharmacologic options for VTE prophylaxis include unfractionated heparin (UFH), low molecular weight heparins (LMWH), warfarin, factor Xa inhibitors, and indirect or direct thrombin inhibitors. UFH may be administered intravenously or subcutaneously and LMWH are typically given subcutaneously. Recently, new oral anticoagulants that directly inhibit thrombin or activated factor Xa have been approved for VTE prophylaxis and for prophylaxis of systemic embolism and stroke in atrial fibrillation (AF) (Eriksson et al., 2011). These agents have a once or twice daily fixed-dose oral regimen and do not require routine anticoagulant monitoring. Dabigatran, rivaroxaban, and apixaban are some of the new anticoagulants that have been studied for DVT prophylaxis in patients undergoing knee or hip surgery but have not been studied in a wide variety of surgical or medical patients. Among the limitations of these agents are cost and ease of reversibility of their anticoagulant effects, especially in the context of trauma or urgent neurosurgical interventions (Cotton et al., 2011). At this time, VTE pharmacologic prophylaxis typically consists of either UFH or LMWH (Geerts et al., 2008; Kearon et al., 2008) (Table 20.2). Enoxaparin and dalteparin are the most commonly used LMWH in the US. Warfarin, at low doses, is often used as an alternative in patients undergoing hip or knee surgery. For pharmacologic VTE prophylaxis, UFH is administered two or three times daily. The higher dose is slightly more effective with a slightly greater bleed risk. LMWH, by comparison with UFH, is superior for VTE prophylaxis because of a relative risk reduction (RRR) of 58% to 68% for VTE, lower risk of recurrent VTE (RRR 53–68%), lower risk of death (RRR 47%), and a decreased risk of bleeding complications. LMWH has a longer half-life compared to UFH and greater bioavailability, longer duration of action, and less variability in activity because LMWH has a greater ratio of antifactor Xa to antifactor IIa and fewer nonspecific binding proteins. While there has been some concern that LMWH may have a greater bleeding risk because of their greater potency and longer duration, there are no data to support that LMWH conveys a greater risk of bleeding, at least in neurosurgical patients, in whom enoxaparin was reviewed (Browd et al., 2004).
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Table 20.2 Selected drugs for venous thromboembolism treatment or pharmacologic prophylaxis and their doses For deep vein thrombosis or pulmonary embolism prophylaxis: 1. Unfractionated heparin 5000 units subcutaneously (SC) two or three times daily 2. Enoxaparin: ● 40 mg SC daily for venous thromboembolism prophylaxis ● For patients with reduced creatinine clearance (75 years old) and patients with low bodyweight (
Chapter 20
Venous thromboembolism in neurologic disease MICHAEL J. SCHNECK* Departments of Neurology and Neurosurgery, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
INTRODUCTION Patients with systemic venous thromboembolism (VTE) can present with superficial venous thrombosis (SVT), deep venous thrombosis (DVT), or pulmonary embolism (PE). Both SVT and DVT may occur as partial or total occlusions of draining veins of the upper or lower extremities. SVT and DVT are of concern because of the potential risk of thrombophlebitis and propagation of emboli to the pulmonary circulation. PE is of concern because occlusion of the pulmonary vessels can lead to hypoxia, right heart strain, and death. The risk of PE is far greater from DVT than from SVT. As many as 10–25% of patients with DVT will die from subsequent PE (Danish et al., 2004). Without treatment, PE will lead to significant morbidity and mortality, with a 7 day mortality as high as 75% (Geerts et al., 2008). Patients with neurologic disease, or those undergoing procedures for a neurologic or neurosurgical condition, have a very significant VTE risk. Thus, awareness of this risk is critical to prevent the subsequent complications related to VTE.
EPIDEMIOLOGY (WITH SPECIFIC FOCUS ON NEUROLOGIC DISEASE) About 600 000 patients develop a new DVT each year in the US (Browd et al., 2004; Danish et al., 2004; Geerts et al., 2008). One third of these patients are diagnosed with an isolated lower extremity DVT and these DVTs are the primary etiology leading to PE (Browd et al., 2004; Geerts et al., 2008). In the US, the annual PE rate is 1–2 per 1000 persons with an estimated attributable case-fatality rate of 200 000 hospitalized patients (Kearon et al., 2008). Almost 25% of all patients with
PE die suddenly, and the survival rate of the remainder is only 71% (Heit et al., 1999). Presumed asymptomatic DVT is not “benign,” with an estimated rate of fatal PE from these DVT ranging from 13% to 15% (Giannoukas et al., 1995; Heit et al., 1999). While calfvein thrombosis, compared with above the knee thrombosis, has a lower case-fatality rate, it has a 40–50% risk of extension into proximal leg veins (Geerts et al., 2008; Decousus et al., 2010; Lautz et al., 2010). Of note, an 844 patient series with below the knee venous thrombosis found that 24.9% had concomitant DVT or PE (Lautz et al., 2010). Additionally, of 600 patients with isolated SVT, 10.2% developed thromboembolic complications at 3 months, though 90.5% had been treated with anticoagulants (Decousus et al., 2010). Upper extremity DVT is also a significant, albeit less known source, with case rates upwards of 13.5%, mainly attributable to peripherally inserted central catheters and central venous lines. While upper extremity DVT is less common than lower extremity DVT, the risk of PE is high, at 36%, for all upper extremity DVT (Hingorani et al., 1997). There are a number of risk factors for VTE, as listed in Table 20.1. Population risk factors for first-ever VTE in the Copenhagen City Heart Study included obesity, cigarette use, male sex, socioeconomic status, and diastolic arterial blood pressure greater than 100 mmHg (Holst et al., 2010). Hereditary and acquired thrombophilias include activated protein C resistance, factor V Leiden mutation, prothrombin G20210A mutation, antiphospholipid antibodies, lupus anticoagulant, elevated factor VIII levels, protein C or protein S deficiency, hyperhomocysteinemia, dysfibrinogenemia, antithrombin deficiency, and heparin-induced thrombocytopenia (Rees et al., 1995; Rosendaal et al., 1995, 1998; Wahl et al., 1998; Runchey
*Correspondence to: Michael J. Schneck, M.D., Professor of Neurology and Neurosurgery, Loyola University Chicago, Stritch School of Medicine, Maguire Building, Suite 2700, 2160 South First Avenue, Maywood, Illinois 60153, USA. Tel: þ1-708-216-2662, Fax: þ1-708-216-5617, E-mail: [email protected]
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Table 20.1 Risk factors for deep vein thrombosis or pulmonary embolism Inherited and acquired thrombophilias Surgery (most commonly lower extremity orthopedic and pelvic surgeries) Indwelling central venous catheters and peripherally inserted central catheter lines Major trauma Prolonged paralysis Age >60 years old Oral contraceptive use Hormone replacement use Malignancies Chemotherapy use Heart disease Ischemic or hemorrhagic stroke Nephrotic syndrome Prior history of venous thromboembolism Family history of venous thromboembolism
et al., 2002; Browd et al., 2004; Lijfering et al., 2010). The leading cause of acquired (as opposed to hereditary) thrombophilias is the antiphospholipid (APL) syndrome. The risk of venous thrombosis is higher with the APL syndrome in the presence of a concomitant lupus anticoagulant. The VTE risk associated with hereditary, acquired, or mixed thrombophilia of is not clear, but factor V Leiden and prothrombin G20210A mutations are among the thrombophilic markers for which there is a very strong association (Rees et al., 1995; Rosendaal et al., 1995, 1998; Lijfering et al., 2010). The factor V Leiden mutation is the most common prothrombotic mutation in Caucasians but is very rare in Asians and African Americans (Rees et al., 1995; Lijfering et al., 2010). The prevalence of factor V Leiden mutation is approximately 5%, and that of the prothrombin G20210A mutation is approximately 2% in white patients. Heterozygous patients with factor V Leiden mutations have a fivefold to sevenfold increased VTE risk, whereas heterozygous prothrombin G20210A carriers have a threefold to fourfold higher VTE risk. Double heterozygous carriers of factor V Leiden and the prothrombin G20210A mutation have a 20-fold increased risk of first-ever VTE, and homozygous factor V Leiden carriers have an 80-fold increased VTE risk. Heterozygous carriers of each mutation alone do not have an increased risk compared to noncarriers (Lijfering et al., 2010). Hospitalized patients are at particular risk for VTE which has been deemed to be one of the most preventable causes of inpatient mortality. The American College of Chest Physicians (ACCP) 2008 guidelines estimate a
hospital prevalence of VTE ranging from 10% to 40% in moderate-risk patients and a prevalence as high as 80% among high-risk patients (Geerts et al., 2008). Neurologic and neurosurgical disease is highly associated with an increased VTE risk in hospitalized patients. Neurologic impairments are present in about 7% of all immobile inpatients at risk for VTE (Gaber, 2007). DVTs may be present in 15–40% of all hospitalized neurosurgical patients, 40–80% of all patients with major head trauma, and 20–40% of all hospitalized stroke patients. Patients with spinal cord injury, not treated with prophylactic anticoagulation, have a particularly high DVT rate of approximately 60–80% (Browd et al., 2004). Patients with head injury have a reported DVT rate as high as 31.6%, though the DVT rate is lower, at 25.5%, among patients with isolated head injuries (Rogers et al., 2002; Sharma et al., 2007). Older age, subarachnoid hemorrhage, associated lower extremity injury, and higher injury severity scores have been associated with increased risk in patients with moderate to severe brain injury (Sharma et al., 2007). These patients with traumatic injuries and a high DVT rate are also at particularly high risk for PE because patients with head trauma also have relative contraindication to pharmacologic prophylactic anticoagulation (Rogers et al., 2002; Sharma et al., 2007). The overall incidence of DVT in neurosurgical patients is highly variable but may be as high as 50% (Auguste et al., 2004; Browd et al., 2004). The incidence of PE ranges from 1.5% to 5%, with a 9–50% related risk of death (Auguste et al., 2004; Browd et al., 2004). In elective neurosurgical and spine procedures, the risk of DVT is much lower, particularly if patients receive pharmacologic prophylaxis (Sansone et al., 2010). In Japan, the risk of symptomatic VTE in neurosurgical patients is only 0.07–0.22%, but in one small 37 patient series, the lower extremity DVT rate was 13.5% with 60% of those five DVT patients having an asymptomatic PE (Taniguchi et al., 2009). Thus, ascertainment bias remains a problem in determining the true rate of VTE in neurosurgical patients. VTE risk factors in neurosurgical patients include concomitant hemorrhagic or ischemic stroke, spinal cord injury, benign or malignant CNS tumors, the duration of the surgical procedure, and the general duration of hospital immobility (Hamilton et al., 1994; Rogers et al., 2002; Browd et al., 2004; Danish et al., 2004; Sharma et al., 2007; Ageno et al., 2009; Carlile et al., 2010; Ekeh et al., 2010). For spine surgery, the type of case may reflect the underlying VTE risk. A large series of 108 419 cases from the Scoliosis Research Society morbidity and mortality database, reported the 2004–2007 complication rates related to clinically evident VTE for lumbar microdiscectomy, anterior cervical discectomy and fusion, and lumbar
VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE 291 spinal stenosis decompression. The rate of the DVT rate histologic grade 4 tumor, and prolonged surgery (longer was 1.18/1000 and the PE rate was 1.38/1000 cases with a than 4 hours). Mortality is also higher for astrocytoma mortality rate of 0.34/100 cases. The rates were lowest patients with VTE, with a 30% increased risk of death for lumbar microdiscectomy, and highest for spine prowithin 2 years (Browd et al., 2004). The risk of VTE is cedures for metastatic tumors (Smith et al., 2010). The lower in other tumor types but is not insignificant. risk of PE may also be higher in patients undergoing VTE has been recognized as one of the more common combined anterior and posterior surgeries as compared complications in patients with meningiomas though the with posterior spine surgery only (Ozturk et al., 2010). rate is relatively low for this tumor type. Sughrue Overall, the VTE rate in neurosurgical patients is not et al. (2011) reported a series of 834 patients who underhigh. A meta-analysis of patients undergoing elective went craniotomy for meningioma in which 57 (6.8%) had neurosurgical procedures noted that the DVT rate was serious medical complications with a reported clinically just 1.09% and the PE rate was 0.06% ( Sansone et al., symptomatic VTE rate of 0.8% (7/834). 2010). For neurosurgical patients with cancer, however, Stroke patients are also at very high risk for VTE. the VTE rates are much higher. In general, cancer conTong et al. (2010) reported that the prevalence rate of veys upon all patients a particularly significant VTE risk, DVT was 0.8% and the rate of PE was 0.3% for all but patients with central nervous system (CNS) tumors patients hospitalized with ischemic stroke as a primary are at particularly high risk (Hamilton et al., 1994; diagnosis. Medical complications were associated with Semrad et al., 2007). Patients with an intracranial tumor, an increased hospital length of stay in this cohort. Over in an Australian series of 2279 patients treated only with the period from 1998 to 2007, the overall length of stay of sequential compression devices (SCDs), had a higher hospitalized stroke patients declined but remained VTE rate than patients with spinal cord tumors. While unchanged for those patients with medical complicathe overall rate in this series was low; there was a roughly tions (including DVT or PE, stroke-related myocardial 3% VTE rate among the patients with intracranial tumors infarction, or pneumonia). Early stroke-related DVT (Smith et al., 2004). Cumulative rates of symptomatic was studied in a series of 278 ischemic and 12 hemorVTE as high as 30% may occur in patients with brain rhagic stroke patients who underwent venous duplex tumors (Perry et al., 2010). It is hypothesized that ultrasonography (VDU) on day 3 and day 9 (Bembenek tumor-induced hypercoaguable states may be present et al., 2011). DVT occurred in 8% of these stroke patients in patients with malignant astrocytoma, especially in with 83% (24/29) of DVTs occurring at day 3. A subsethe context of higher grade tumors. This VTE risk in quent 3% (9/299) had new onset DVT at day 9. These patients with astrocytoma is attributed to specific coagnewly discovered DVTs increased the risk of 3 month ulation abnormalities, including elevated fibrinopeptide mortality with an odds ration (OR) of 12.4 (95% CI A, elevated fibrinogen fragment Bb 15-32, and 1.72–89.4). Adjusted for stroke severity and prestroke decreased activated partial thromboplastin times with disability, an elevated serum C-reactive protein (CRP) resultant increases in procoagulant activity and platelet was associated with increased risk of DVT (OR 8.75; activation (Hamilton et al., 1994). The astrocytoma95% CI 1.61–47.6) (Bembenek et al., 2011). The risk is associated VTE rate depends upon a number of factors related both to immobility and to a greater risk for hyperincluding ascertainment biases related to the diagnosis coagulable states in patients with stroke. Patients with and associated prophylaxis regimens. Among 9489 cases cryptogenic stroke or transient ischemic attack (TIA) of hospitalized patients with malignant glioma hospitalmay also have a greater risk of silent PE. Patients who ized during a 6 year period in California, the cumulative had a patent foramen ovale (PFO) and underwent V/Q 2 year incidence of VTE was 7.5% with 55% being diagscans were identified from a stroke registry. The evalunosed within 2 months of surgery. Risk factors included ation included 151 patients from the 266 patient registry. histology of glioblastoma multiforme (GBM), older age, In 35% of the patients, a silent PE was found (56/151), and three or more chronic associated medical conditions. though a DVT was identified in only 7% (11/151) of the The presence of VTE conveyed a greater risk of death patients. An atrial septal aneurysm was independently within 2 years (HR 1.3 95% CI 1.2–1.4) (Semrad et al., associated with PE. There was also an association with 2007). VTE rates in the 6 weeks after surgery range from oral contraceptive use and PE among the women in this 3% to 60% (Semrad et al., 2007). Beyond this 6 week series of PFO-related stroke (Tanislav et al., 2011). postoperative period, the VTE rate remains high in astroIn stroke patients, clinical prediction models based on cytoma patients, with symptomatic DVT rates of 24% clinical factors alone were unable to identify immobile reported over the 17 months following initial surgery stroke patients at low versus high risk for DVT (Semrad et al., 2007). Patients with astrocytoma and (Dennis et al., 2011). DVT is a clinically significant comthe following risk factors have a higher VTE risk: age plication in these patients, however. Approximately 75% older than 60 years, larger tumor size, chemotherapy, of patients may develop DVT without prophylaxis
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(Kelly et al., 2001; Adams et al., 2007; Sherman et al., 2007; Kase et al., 2009). PE is also a significant cause of mortality in stroke patients, with upward of 25% of early poststroke deaths attributable to PE (Kase et al., 2009). Most fatal PE occurs within 2–4 weeks after an ischemic stroke. The diagnosis of PE can be challenging in stroke patients who have accompanying cognitive deficits, dysphagia, or speech impairments, and concomitant pneumonia or fever. A high index of clinical suspicion is particularly needed in stroke patients (Kumar et al., 2010). Patients with hemorrhagic stroke have a VTE rate that is roughly 65% higher than patients with ischemic stroke (Skaf et al., 2005). In a single center retrospective series of patients treated for aneurysmal subarachnoid hemorrhage (SAH), the incidence of asymptomatic DVT was 24% in patients who had surveillance screening by VDU. Risks for DVT were higher with greater Hunt and Hess aneurysmal SAH scores, length of ICU stay, and total length of hospital stay (Ray et al., 2009). Patients with neuromuscular and neurodegenerative diseases also have a high VTE risk particularly because of immobility but also because patients with autoimmune states have a greater risk for hypercoagulability (Ageno et al., 2009). The actual incidence in many of these neurologic diseases is not well studied (Ageno et al., 2009). VTE risk was elevated in a number of autoimmune diseases (Ramagopalan et al., 2011). Among them were multiple sclerosis, myasthenia gravis, and dermatomyositis or polymyositis. For multiple sclerosis, the rate ratio ranged from 2.14 to 2.52 in the cohorts studied. For myasthenia gravis, the rate ratio ranged from 2.04 to 2.34. For dermatomyositis or polymyositis, the rate ratio ranged from 1.98 to 3.04. By comparison, the highest rates in this study were seen for systemic lupus erythematosus (rate ratios of 3.61–4.60) and polyarteritis nodosa (rate ratios of 2.88–5.36). Multiple sclerosis patients who are at particular risk for DVT are those who are bedridden or wheelchair bound. In one series of 132 patients, the average duration of illness was 18.7 years and only 25 patients were able to walk with even some assistance. A total of 113/132 patients had lower limb edema. All of these 132 patients had VDU and a DVT was found in 58 patients (43.9%). A total of 32 had a prior history of DVT. D-dimer levels were elevated in 45% (26/58) of patients with DVT and 35% (26/ 74) of patients without DVT. Of note, a number of multiple sclerosis patients had elevated D-dimer with VDU negative DVT. The converse was also true. Thus, D-dimer values may be of limited utility in excluding VTE in multiple sclerosis patients (Arpaia et al., 2010) For Parkinson disease, in a study of 81 patients, the asymptomatic DVT rate, determined by VDU, was 4.9 % (Burbridge et al., 1999). In a Mayo Clinic study
of the morbidity associated with 114 Guillain–Barre´ patients admitted to an intensive care unit, the incidence of DVT was 4%, and the incidence of PE was 3%. The exact details are unknown but the authors suggested that most, if not all, of the patients were on some form of pharmacologic prophylaxis. (Henderson et al., 2003). A retrospective study of 73 patients with Guillain–Barre´ syndrome reported an incidence of symptomatic DVT of 7% (five patients with DVT; three of whom also had PE) (Gaber et al., 2002). Fifty of the 73 patients were on pharmacologic prophylaxis. Of the five patients with DVTs, two were not anticoagulated and the other three were on enoxaparin. Finally, patients who receive intravenous immunoglobulin (IVIG) treatment for neurologic diseases are also at increased risk for thromboembolism complications including VTE (Hommes et al., 2004; Vucic et al., 2004)
GENERAL PRINCIPLES Presentation and diagnosis Frequently, patients with VTE will not have apparent clinical symptoms or have symptoms or signs that can be indistinguishable from other disease states. Thus, for example, extremity swelling due to DVT may be attributed to dependent edema due to paralysis, and pain and burning due to DVT may be attributed to neuropathy in some patients. The classic symptom onset of a DVT is that of an acute painful, enlarged, swollen, and erythematous extremity, but some 50–60% of patients will not have clinical symptoms (Danish et al., 2004). Additionally, a Homan’s sign may be present, but the accuracy of the Homan’s sign is very unreliable with both low sensitivity and specificity. Estimates are that this sign is present in only 33% of patients with DVT, with an accuracy ranging from 8% to 50% for patients with DVT (Urbano, 2001). Similar to DVT, almost 50% of patients with PE have no apparent clinical symptoms. In those instances, PE is typically found in the context of an initial DVT diagnosis (Geerts et al., 2008). The classic symptom presentation of PE includes pleuritic chest pain, variable degrees of shortness of breath, and cardiac dysrhythmias or sinus tachycardia. The signs and symptoms may help to assess pretest probability for PE but are not sufficiently accurate for the exclusion of PE. In these circumstances, arterial blood gases and electrocardiogram may be suggestive but are also not sufficiently accurate to exclude PE. Echocardiography may further hint at a possible PE if there are signs of increased pulmonary arterial pressures such as right heart strain (McConnell’s sign) though this is not a specific sign for PE (Torbicki, 2005). Elevated D-dimers are found in most patients with VTE but may also be present in patients with acute
VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE stroke, myocardial infarction, malignancy, or autoimmune states; patients undergoing recent surgery; or patients with recent history of trauma. Thus the utility of a negative D-dimer serum assay is to further exclude patients at low or intermediate probability for VTE in the outpatient setting (Wells et al., 2003; Thachil et al., 2010). While a positive D-dimer is not diagnostic, a negative D-dimer has a negative predictive value of 99% (Wells et al., 2003). The D-dimer assay is much less useful in the diagnosis of VTE in hospitalized patients where false-positive tests are common (Thachil et al., 2010). Ultimately, the diagnosis of DVT or PE is dependent on confirmatory imaging tests. Contrast venography is the nominal gold standard for the diagnosis but is rarely used because of limited availability, cost, patient discomfort, and a significant risk of contrast-induced thrombosis (Browd et al., 2004; Miller and Lee, 2005). Impedance plethysmography is also rarely used as it does not help to identify nonocclusive thrombus and cannot easily find calf-vein thrombosis. Thus, the mainstay for DVT diagnosis and screening is venous duplex ultrasonography (VDU) (Taniguchi et al., 2009). VDU is a readily available tool that is 89–96% sensitive and 96–100% specific in the diagnosis of significant DVT. VDU has a lower sensitivity (75%) for isolated calf DVT (Browd et al., 2004; Giannoukas, et al., 1995; Stein et al., 2010). In addition to widespread availability at most hospitals, VDU is relatively less expensive, portable, and noninvasive. It can therefore be used in a wide variety of settings including the intensive care unit, emergency department, and ambulatory clinics. Limitations of VDU include dependence on operator skill and problems in visualizing the veins in certain patients. VDU also cannot adequately visualize iliac or pelvic veins. The use of VDU, along with clinical prediction rules, improves the DVT likelihood ratio with a specificity of 98–100% to 0.2 among low-risk patients, 1.3 among moderate-risk patients, and 3.3 among highrisk patients (Thachil et al., 2010). In this regard, MR venous imaging has a distinct advantage compared to VDU for imaging the iliac and other pelvic veins and is also more accurate for imaging of below the knee DVT. When compared to conventional venography, MR imaging has an estimated sensitivity of 91.5% and specificity of 94.8% in pooled estimates for detection of lower extremity DVT. The sensitivity is higher for proximal DVT as opposed to distal DVT (Sampson et al., 2007). MR imaging is still superior to CT venography or VDU. Using MR imaging as the reference standard, VDU has a sensitivity of 93.5% and specificity of 98.0%, and CT venography has a sensitivity of 89–100% and specificity of 94–100% (Sampson et al., 2007; Miller and Lee, 2005). The limitations of MR venography are cost and limited availability.
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Pulmonary angiography is the “gold standard” for the diagnosis of PE. Ventilation/perfusion (V/Q) scans and spiral or helical CT angiography are less invasive and so these are the preferred modalities (PIOPED Investigators, 1990; Coche et al., 2001). The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study demonstrated that a normal V/Q scan excluded PE with high sensitivity and specificity. (PIOPED Investigators, 1990) In this study, a high probability V/Q scan had a 95% positive predictive value for those patients where there was a strong clinical suspicion for PE. In 40–70% of patients, however, a low or intermediate probability V/Q scan result occurred and so V/Q scans were nondiagnostic for exclusion of PE in many patients where there was an intermediate or high pretest PE probability (Kearon et al., 2008). In these patients, further testing that includes DVT screening and/or pulmonary angiography is indicated if there is a sufficiently high suspicion for PE. Unfortunately, high probability V/ Q scan results occur in only 41% of patients with angiographically proven PE, and a negative lower extremity ultrasound occurs in 40% of angiographically proven PE. Conversely, a negative D-dimer assay and a negative lower extremity duplex ultrasound are associated with a negative predictive value of greater than 99% in making a negative diagnosis of PE (Coche et al., 2001; Thachil et al., 2010). Spiral CT is probably superior to V/Q scans for detection of PE. V/Q scans, however, have an advantage in patients who do not have reasonable kidney function or who have contrast dye allergy, for whom spiral CT is therefore contraindicated (Coche et al., 2001). On CT, a pulmonary artery occlusion appears as either a partial or complete filling defect (Fig. 20.1). Spiral CT has a sensitivity of 99% and a specificity of 95% compared to the gold standard of pulmonary angiography (Coche et al., 2001). MR angiography (MRA) of the pulmonary vessels is also an option but is not superior to spiral CT (Stein et al., 2010). The Wells criteria are a useful clinical prediction tool for identifying patients at high risk for VTE. Separate prediction tools exist for DVT and PE (Wells et al., 1997, 2001; Thachil et al., 2010). Among the risk factors incorporated into the DVT prediction tool are: active cancer, asymmetric pitting edema, swelling of the entire leg, asymmetric calf swelling, presence of nonvaricose superficial veins, paralysis or leg immobilization, bedridden > 3 days, history of major surgery in the prior 4 weeks, localized tenderness along the deep venous distribution, and presence of nonvaricose collateral superficial veins. Risk factors incorporated in the Wells predictive criteria for PE without diagnostic imaging include: active cancer, clinical signs of DVT, hemoptysis, tachycardia, immobilization including paresis or
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Fig. 20.1. A 73-year-old woman with a longstanding history of tinnitus and right hearing loss of undetermined etiology had a syncopal episode. At an outside hospital a CT scan revealed a large right cerebellopontine angle mass. On admission, she underwent an echocardiogram for evaluation of the syncope. This echocardiogram showed a hypokinetic right ventricle with decreased contractility sparing the apex (McConnell’s sign). A spiral CT of the pulmonary vessels (coronal cut below) was then obtained. This revealed filling defects with the appearance of pulmonary emboli noted bilaterally in both pulmonary arteries branching into several segmental arteries consistent with multiple pulmonary emboli. There was also mild dilatation of the right pulmonary artery.
leg paralysis, bedridden > 3 days, history of major surgery in the prior 4 weeks, prior DVT or PE, and an alternative diagnosis that is less likely than PE. Additional clinical and historical risk factors conveying particular high risk of DVT or PE include: age 75 years or older, acute spinal cord injury with paralysis, elective major lower extremity surgeries, leg, hip or pelvis fractures, prior history of stroke or trauma, and prior history of VTE (Bahl et al., 2010). Increased risk associated with thrombophilia history or markers were: a history of congenital or acquired thrombophilias, a family history of thrombosis, presence of prothrombin G20210A, factor V Leiden mutations, elevated homocysteine levels and acquired thrombophilias including a positive lupus anticoagulant, and elevated anticardiolipin antibodies.
General treatment issues PROPHYLAXIS Mechanical and/or pharmacologic thromboprophylaxis clearly decreases the incidence of VTE, and all-cause mortality, in hospitalized patients. There are defined advantages and disadvantages for both mechanical
and pharmacologic prophylaxis. Additionally, there may be risk/benefit profile differences between the various pharmacologic agents used for VTE prophylaxis, particularly related to the risk of hemorrhagic complications. This risk of hemorrhagic complications is particularly problematic in patients with neurologic or neurosurgical disease, and the guidelines for VTE prophylaxis established in the general medical and surgical population may not be easily extended to the neurologic patient population (Geerts et al., 2008). VTE prophylaxis entails mechanical prophylaxis, pharmacologic prophylaxis or a combination of both modalities. Mechanical prophylaxis that is achieved by early ambulation, intermittent pneumatic compression (IPC), or sequential compression devices (SCD), has been shown to decrease the risk of DVT (Agnelli et al., 1998; Rogers et al., 2002; Geerts et al., 2008; Kearon et al., 2008; Taniguchi et al., 2009; CLOTS II Investigators 2010; Morris and Woodcock, 2010; Sachdeva et al., 2010). The utility of graduated compression stockings has been debated. A Cochrane metaanalysis of 18 studies suggested that the use of graduated elastic compression stockings was of benefit when used with additional prophylactic therapies (Sachdeva et al., 2010). The CLOTS II (Clots in Legs Or sTockings after Stroke) trials (CLOTS Investigators, 2010) suggested that thigh-length stockings were more effective than below-the-knee stockings in patients with stroke screened by VDU at 7–10 days and 15–20 days posthospitalization. The CLOTS II study reported a proximal DVT rate of 6.3% for thigh-length stockings and 8.8% for below-the-knee stockings. However, skin breakdown occurred in 3.9% of those with thigh-length stockings and in only 2.9% of those with below-the-knee stockings. A caveat of the CLOTS II study was that the results of the CLOTS Trial I of thigh-length stockings versus placebo were not associated with a clinically significant reduction in proximal DVT but were associated with significant skin breakdown events (Dennis et al., 2009). Compression devices (either intermittent pneumatic compression (IPC) or sequential compression devices (SCDs)), may be used with or without elastic stockings. These devices are assumed to prevent DVT by promoting hemodynamic flow and fibrinolytic function. These devices are associated with low risk, though there is a concern that thrombus may be dislodged by an SCD in patients with have undetected or pre-existing extremity thrombus. A systematic review suggested that IPC/ SCD may be associated with a decrease in the rate of DVT but the evidence is weak (Agnelli et al., 1998; Rogers et al., 2002; Kearon et al., 2008; Morris and Woodcock, 2010). The main advantage of mechanical prophylaxis is a reduced risk of bleeding. These devices, however, are still associated with a high rate of DVT.
VENOUS THROMBOEMBOLISM IN NEUROLOGIC DISEASE Among neurosurgical patients treated with SCDs, the DVT rate is as high as 32% (Taniguchi et al., 2009). By contrast, the rate of DVT using pharmacologic prophylaxis in a similar population is much lower. Even with the use of pneumatic compression devices, the incidence of DVT is high with reported rates of 32% in neurosurgical patients. Pharmacologic thromboprophylaxis, however, is associated with a reduction of DVT incidence by up to 50% (Agnelli et al., 1998; Geerts et al., 2008). Pharmacologic options for VTE prophylaxis include unfractionated heparin (UFH), low molecular weight heparins (LMWH), warfarin, factor Xa inhibitors, and indirect or direct thrombin inhibitors. UFH may be administered intravenously or subcutaneously and LMWH are typically given subcutaneously. Recently, new oral anticoagulants that directly inhibit thrombin or activated factor Xa have been approved for VTE prophylaxis and for prophylaxis of systemic embolism and stroke in atrial fibrillation (AF) (Eriksson et al., 2011). These agents have a once or twice daily fixed-dose oral regimen and do not require routine anticoagulant monitoring. Dabigatran, rivaroxaban, and apixaban are some of the new anticoagulants that have been studied for DVT prophylaxis in patients undergoing knee or hip surgery but have not been studied in a wide variety of surgical or medical patients. Among the limitations of these agents are cost and ease of reversibility of their anticoagulant effects, especially in the context of trauma or urgent neurosurgical interventions (Cotton et al., 2011). At this time, VTE pharmacologic prophylaxis typically consists of either UFH or LMWH (Geerts et al., 2008; Kearon et al., 2008) (Table 20.2). Enoxaparin and dalteparin are the most commonly used LMWH in the US. Warfarin, at low doses, is often used as an alternative in patients undergoing hip or knee surgery. For pharmacologic VTE prophylaxis, UFH is administered two or three times daily. The higher dose is slightly more effective with a slightly greater bleed risk. LMWH, by comparison with UFH, is superior for VTE prophylaxis because of a relative risk reduction (RRR) of 58% to 68% for VTE, lower risk of recurrent VTE (RRR 53–68%), lower risk of death (RRR 47%), and a decreased risk of bleeding complications. LMWH has a longer half-life compared to UFH and greater bioavailability, longer duration of action, and less variability in activity because LMWH has a greater ratio of antifactor Xa to antifactor IIa and fewer nonspecific binding proteins. While there has been some concern that LMWH may have a greater bleeding risk because of their greater potency and longer duration, there are no data to support that LMWH conveys a greater risk of bleeding, at least in neurosurgical patients, in whom enoxaparin was reviewed (Browd et al., 2004).
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Table 20.2 Selected drugs for venous thromboembolism treatment or pharmacologic prophylaxis and their doses For deep vein thrombosis or pulmonary embolism prophylaxis: 1. Unfractionated heparin 5000 units subcutaneously (SC) two or three times daily 2. Enoxaparin: ● 40 mg SC daily for venous thromboembolism prophylaxis ● For patients with reduced creatinine clearance (75 years old) and patients with low bodyweight (
