Abbreviations
aPTT
activated partial thromboplastin time
CSCM
Consortium for Spinal Cord Medicine
CT
computed tomography
CTPA
CT pulmonary angiography
CUS
compression ultrasonography
DVT
deep venous thrombosis
GCS
graduated compression stockings
IPCD
intermittent pneumatic compression device
IVCF
inferior vena cava filter
LMWH
low-molecular-weight heparin
MRI
magnetic resonance imaging
PE
pulmonary embolism
PESI
pulmonary embolism severity index
SCI
spinal cord injury
UH
unfractionated heparin
VKA
vitamin K antagonists
VTE
venous thromboembolism
Introduction
The classical Virchow’s postulate links the occurrence of venous thromboembolism (VTE) to the presence of a disruption of the circulatory flux, a damage of the endothelial tissue, or a hypercoagulability state. Immobility and palsy are prominent risk factors for VTE and are frequently seen in clinical rules used for its diagnosis ( ). Individuals with a spinal cord injury (SCI) present frequently not only with impaired mobility due to the associated neurological motor deficit, but endothelial injuries and a hypercoagulability condition may also arise as a consequence of the lesion mechanism, such as trauma or neoplasms, as well as secondary complications like infections or pressure ulcers ( ; ) ( Fig. 1 ). Thus, SCI is associated with an increased risk of venous thromboembolism in its acute phase that may extend to its chronic phase ( ; ; ).
Many advances have been made regarding risk stratification for prophylaxis and diagnostic algorithms for VTE in the general population. The proposed strategies and clinical rules however have not been validated for individuals with SCI, posing a challenge for physicians involved in the care of such patients.
Epidemiology
The reported prevalence of VTE in spinal cord injury is variable. A study by based on screening in asymptomatic patients with serial scintigraphy with labeled fibrinogen identified clots in 100% of the 20 studied patients. Other studies that are based on clinical symptoms or less sensitive screening methods report a prevalence of 10% to 15% for deep venous thrombosis (DVT) and 5% to 10% for pulmonary embolism (PE).
The risk appears to be the highest in the first 12 weeks after the injury ( ; ), with a retrospective cohort study by reporting a 17 times risk increase for DVT and 3.5 times for EP within 3 months after an SCI in comparison to age- and sex-matched individuals from the general population. A study by , however, didn’t find an increased risk in the first 3 days after the lesion. It is postulated that factors like the flaccid paralysis occurring during the spinal shock phase and the need for immobilization secondary to multiple trauma may be of significance in the augmented risk during the acute stage of SCI ( Fig. 2 ). Moreover, the dysregulation of the autonomic nervous system may lead to an imbalance of the hemostatic and fibrinolytic systems, and there is evidence of increased platelet reactivity to collagen and an imbalance in factor VIII to factor VIII-C ration ( ).
Published data on the incidence of VTE during the sub-acute and chronic phases of SCI are conflicting. There appears to be a reduction in this risk, approaching that of the general population, although somewhat higher. A study by reported an incidence of 34.4 VTE events per 100,000 patient-year during the first 90 days which was reduced to 0.3 events per 100,000 patient-year thereafter. Data from a systematic review indicate a PE incidence ranging from 0.5% to 6.0% and a DVT incidence between 2.0% and 8.0% in the sub-acute phase in patients under different prophylaxis strategies ( ). The above-mentioned study by reported a cumulative risk of 1.19 times after the first year of the SCI, and studies evaluating individuals in the chronic stage demonstrated DVT incidences as low as 0.55 per 10,000 patients-day ( ) and as high as 8% ( ) in patients admitted for rehabilitation treatment.
Without adequate treatment, the estimated mortality rates may reach 8% for DVT and 25% for PE. In studies performed with individuals with SCI, VTE may be responsible for up to 3% of all the deaths in those admitted for rehabilitation ( ). In addition, individuals affected by VTE may present further clinical complications such as post-thrombotic syndrome, pulmonary hypertension, and recurrent VTE events ( ).
Screening
The rationale for screening for asymptomatic VTE is based on its high incidence in SCI, therefore being a probable and preventable cause of death during the acute phase. The identification of an asymptomatic thrombus could then lead to immediate treatment, which could hinder further complications. Proposed approaches involve performing serial lower limb duplex ultrasound ( ), D-Dimer testing, or both used in combination ( ; ).
Even though the majority of thrombi have an origin in the lower limb circulation, up to half resolve spontaneously within 72 h, and only around a sixth of them lead to disturbance in the deep vein circulation ( ). Screening studies have been successful in demonstrating high sensitivity and in identifying a high number of asymptomatic VTE. As the majority of these were designed as diagnostic and not therapeutic studies, there is uncertainty about the clinical benefits of this strategy which may well lead to overdiagnosis and consequently overtreatment. Considering the bleeding risk associated with therapeutic anti-coagulation, patients might be exposed to unnecessary use of a dangerous medication.
Prophylaxis
Acute phase
Since the 1970s, uncontrolled studies proposed the use of pharmacological prophylaxis in acute SCI ( ). Different approaches involving the use of unfractionated heparin (UH), vitamin K antagonists (VKA), low-molecular-weight heparin (LMWH), intermittent pneumatic compression (IPC) and electrostimulation alone or in different combinations have been tested. In comparison to mechanical prophylaxis alone, the use of pharmacological prophylaxis may lead to an absolute risk reduction of up to 15% in the incidence of VTE during the acute phase of SCI ( ).
The major advantage of LMWH in comparison to UH is related to an average of 4% absolute reduction in the risk of bleeding ( ; ). Enoxaparin was the most frequently used LMWH in clinical trials involving individuals with SCI, but dosing strategies and duration of treatment were greatly varied, from 20 to 40 mg once a day, to 30 mg twice a day, from as little as 14 days up to 8 weeks or longer times based on patient mobility ( ; ; ; ; ; ), preventing these studies from being combined in a meta-analysis. Until now, we could not find any study comparing the same dosing strategy with different durations, allowing a more precise evaluation of the risk-benefit profiles of longer or shorter prophylaxis strategies.
Current guidelines agree that the pharmacological prophylaxis should be initiated as soon as possible during the acute phase, preferably within the first 72 h of the injury, taking into consideration the clinical status and, most importantly, the assessment of the risk of bleeding of the individual patient ( ; ). Recommendations regarding the duration of prophylaxis continue to be at least 8 and up to 12 weeks, which may be prolonged based on the assessment of the individual risk of VTE.
Sub-acute and chronic phase
Studies comparing prophylaxis strategies during the chronic phase of SCI are scarce. It is important to emphasize that in poor resource areas with limited access to specialized care, many individuals with SCI may only be admitted to inpatient rehabilitation already in the chronic phase. The delayed access to rehabilitation services may lead to early complications, such as structured articular mobility restrictions, pressure ulcers, recurrent infections, and obesity, which may further influence the risk of developing a VTE episode ( ).
As discussed above, the risk of VTE decreases after the acute phase. The use of pharmacological prophylaxis is usually safe but encompasses nevertheless an elevation of the patient’s basal risk of bleeding. Minor bleedings (hematomas at the injection site) may occur in up to 64% of patients during rehabilitation ( ), and major bleeding events have been reported in individuals with SCI receiving prophylactic doses of LMWH ( ). We suggest taking into consideration the individual patient risk factors, such as comorbidity, mobility, independence, concomitant use of other medications, presence of infections and near surgical procedures to decide whether or not to initiate the pharmacological prophylaxis. Moreover, as suggested by the , services involved in the care of individuals with SCI should have established policies regarding thromboprophylaxis which should be periodically revised and audited.
Non-pharmacological methods
Maintenance of adequate hydration, early mobilization, physical rehabilitation and promoting independence are classically described as general methods that should be applied to every patient. Intermittent pneumatic compression devices (IPCD) may be used as an alternative prophylaxis method if the risk of complications with the use of pharmacological methods is deemed to be prohibitive ( ). Only a small case series evaluated IPCD without a pharmacological method in individuals with SCI, reporting a 43% incidence of DVT mostly detected by screening, and only 18% of these being a proximal DVT ( ). These devices are used continuously and, therefore, may interfere with the acute rehabilitation program.
A meta-analysis demonstrated that graduated compression stocking (GCS) may be effective in preventing DVT in hospitalized patients, especially those submitted to surgical and orthopedic interventions. This benefit was also seen in those receiving background thromboprophylaxis. Only two studies have used LMWH as background prophylaxis and no difference was found with the addition of GCS. Furthermore, none of the included studies compared GCS alone versus a pharmacological method ( ). Moreover, these devices may cause skin lesions and should not be used in conditions such as peripheral arterial disease and decompensated heart failure.
Current evidence doesn’t support the prophylactic use of inferior vena cava filters (IVCF), and there may be an increased risk of VTE in individuals with SCI who underwent an IVCF implantation, even when receiving pharmacological prophylaxis ( ).
Diagnosis
The usual approach in the individual with suspected DVT or PE involves a clinical evaluation to estimate his pre-test probability based on signs, symptoms and risk factors, followed by a diagnostic strategy to rule in or rule out the diagnosis. The utility of diagnostic algorithms associated with clinical rules such as the Wells’ criteria for DVT or PE, the Geneva score for PE or the PERC have been demonstrated in diverse clinical scenarios ( ), but as of yet, are not validated for individuals with SCI.
Some of the clinical factors evaluated by these rules may have different significance and presentation in SCI ( Table 1 ). Paresis or paralysis may be a major risk factor during the acute phase of an SCI, but this may not extend to the chronic phase. Benign postural lower limb edema is a frequent clinical sign in these individuals and may impair the clinical evaluation of a suspected DVT. Furthermore, the autonomic dysfunction in lesions above T6 may impair tachycardic responses ( ), as evaluated in some scores and pain complaints may be absent due to neurological impairment. In this scenario, it is reasonable to maintain a high level of clinical suspicion.
| Wells’ criteria for DVT |
| Asymmetric leg swelling |
| Whole limb edema |
| Tenderness along the deep venous system |
| Wells’ criteria for PE |
| Heart rate above 100 bpm |
| Geneva score |
| Heart rate above 100 bpm (original score) |
| Heart rate above 94 bpm (revised and simplified scores) |
| Limb pain (revised and simplified scores) |
| PERC rule |
| Heart rate above 100 bpm |
| Unilateral edema |
The test of choice for confirming or excluding the diagnosis will be based on the previously estimated pre-test probability. Moreover, the clinician should also consider how invasive the test is, the availability of the method, and trained staff for performing and interpreting the results and how high the clinical suspicion of DVT or PE is.
D-dimer
The D-dimer is a fibrin degradation product that is positive not only in VTE. Its high sensitivity—especially in quantitative and semi-quantitative tests—in general patients makes it a helpful test for ruling out the diagnosis of both DVT and PE in those with a low pre-test probability ( ). This high sensitivity has been demonstrated in low-quality evidence studies in patients with SCI ( ) and other neurological conditions under rehabilitation treatment ( ), but not as part of a diagnostic algorithm in these populations. The low specificity associated with the test is not enough to confirm the diagnosis; therefore, a positive result will lead to further testing. Despite its high sensitivity in patients presenting a high pre-test probability, a negative result won’t be enough to safely rule out the diagnosis.
Lower limb ultrasonography
Compression ultrasound examination (CUS) is a highly sensitive and specific non-invasive test that may be performed as a point-of-care diagnostic strategy by trained physicians ( ). Based on its widespread availability, non-invasiveness and ease of performance, CUS is the method of choice for the evaluation of patients with moderate or high pre-test DVT probability. This can be performed in strategies that evaluate the proximal venous circulation up to the level of the popliteal vein, requiring a follow-up examination after 1 week if negative, or a complete scan from the common femoral vein down to the deep calf veins, without a need for retesting ( ). Even though there is no specific study on the accuracy of this method in patients in SCI patients, ultrasonography seems like a reasonable method due to its availability and good performance of point-of-care examinations in comparison with expert radiologist evaluation, which may avoid delays in the diagnostic process ( ). For this same reason, lower limb sonography may be an acceptable strategy as a first examination to rule in PE in patients with a higher likelihood of this diagnosis and with clinical signs of DVT ( ), but an isolated negative test is not enough to exclude it.
Lower limb venography
Venography, computerized tomography (CT), and magnetic resonance (MRI) venography are invasive methods requiring the use of contrast. Venography is considered the “gold standard” for the evaluation of the limb venous circulation. Even though a normal venography allows safe withholding of anti-coagulation, it is a limited method due to its restricted availability, costs, discomfort, and difficulties in obtaining standardized and good-quality images and proper evaluation ( ). CT and MRI venography are promising methods that have demonstrated sensitivity and specificity around 95% in meta-analysis, but with high heterogeneity between studies ( ; ). Therefore, they are not considered first-line diagnostic methods but are useful in situations where ultrasonography can’t safely exclude the diagnosis, such as thrombosis in proximal or pelvic veins that are not compressible or in obese patients ( ; ).
CT pulmonary angiography
CT pulmonary angiography (CTPA) has replaced ventilation/perfusion scintigraphy as the method of choice for the diagnosis of PE ( ). With a high sensitivity and specificity, CTPA allows a fast and comprehensive evaluation of the pulmonary circulation and is largely available ( ). It also allows the evaluation of pulmonary images which are useful for differential diagnosis. The constantly evolving technology and quality of images have led to a continual increase in sensitivity and, consequently, in the reported incidence of PE in the general population. This elevation occurred despite the current higher awareness of VTE and adherence to prophylaxis strategies and, according to studies performed in the United States, no concurrent elevation in age-adjusted mortality was observed, which suggests the occurrence of overdiagnosis ( ).
Small thrombus formation is not an infrequent event. One of the physiological functions of the normal lung may be to serve as a clot filter avoiding venous thrombi from reaching the systemic arterial circulation ( ). The physician should, therefore, be aware of the potential risk involved in over-testing patients for PE, for instance, screening patients with a diagnosis of DVT for an asymptomatic PE.
Treatment
Anti-coagulation is the cornerstone of the treatment of VTE ( ). The primary goal of the treatment is to avoid acute complications such as further embolization of deep vein originated thrombi, further impairment of pulmonary function or pulmonary circulation with consequent cardiovascular instability ( ). Adequate quality therapeutic anti-coagulation may also improve late outcomes, such as post-thrombotic syndrome ( ). Affected individuals should receive treatment to achieve rapid anti-coagulation with posterior long-term maintenance with adequate time in therapeutic range (TTR). A summary of commonly used medications is presented in Table 2 .
| Class | Dosing | Effect reversal | |
|---|---|---|---|
| Parenteral agents | |||
| Heparin | UH | Bolus: 80 μg/kg IV Maintenance: 18 μg/kg h IV Adjust dose according to aPTT | Protamine |
| Enoxaparin | LMWH | 1 mg/kg 12/12 h SC | May benefit from protamine use |
| Fondaparinux | Pentasaccharide | < 50 kg: 5 mg SC daily 50–100 kg: 7.5 mg SC daily > 100 kg: 10 mg SC daily | May benefit from andexanet alfa (off label) or activated prothrombin complex concentrate |
| Oral agents | |||
| Apixaban | Factor Xa inhibitor | 10 mg twice daily for 7 days followed by 5 mg twice daily |
|
| Rivaroxaban | 15 mg twice daily for 21 days followed by 20 mg daily | ||
| Edoxaban | 60 mg once daily | ||
| Dabigatran | Direct thrombin inhibitor | 150 mg twice daily |
|
| Warfarin | Vitamin K antagonist | 2–10 mg once daily for 2 days. Adjust according to INR |
|
Initial management
Initial treatment aims to quickly achieve effective anti-coagulation, which can be done both with parenteral and oral agents. Before initiating any anti-coagulant, the risk of bleeding as well as hemodynamic conditions of the individual should be assessed. There’s no validated score for bleeding risk estimation in individuals with SCI receiving anti-coagulant treatment; therefore, a thorough assessment of comorbidities, previous traumas, and surgeries is mandatory ( Table 3 ). For hemodynamically unstable individuals and those who may need urgent or emergent surgery or that may benefit from thrombolytic therapy, the use of short-acting and easily reversible anti-coagulants should be preferred.
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