Venous thromboembolism and anticoagulation in spinal cord lesion rehabilitation inpatients: A 10-year retrospective study

2.1 Patients

We retrospectively collected the data of patients admitted to the Spinal Department of a Rehabilitation Medical Center between 2010 and 2019. Inclusion criteria were age≥18 and admission up to 3 months after traumatic or non-traumatic SCL onset. For traumatic SCL, we defined the lesion onset date as the date of the event, and for non-traumatic SCL, the date on which the neurological deficit first appeared in the medical records. Exclusion criteria were being discharged from the department after less than 1 week and lack of data required for the study analyses.

2.2 Procedure

The sources of participant and SCL data were the records of the Rehabilitation Medical Center and a shared hospital-community database. The data included information on clinical follow-up 1 year or more after SCL onset, and on VTE prevention and outcomes for all participants. The main outcomes were the incidence of clinically diagnosed DVT, PE, clinically significant bleeding events or thrombocytopenia related to anticoagulant treatment, and death, which occurred within 1 year after SCL onset.

The DVT and PE diagnoses were made by clinicians who cared for the participants. They screened the rehabilitation inpatients for SCL complications, including VTE, on a weekly basis. They based DVT diagnosis on clinical symptoms, including swelling, redness, warmth, pain, or tenderness of the limb. They frequently verified the diagnosis with ultrasound. They based PE diagnosis on shortness of breath, unexplained new tachycardia, chest pain, bloody sputum, and/or laboratory blood gas tests, frequently verified by pulmonary CT-angiography.

2.3 Statistical analyses

Patient characteristics and outcomes are described by means and standard deviations (SD) of continuous normally distributed variables; by medians, 25% –75% percentiles, for variables not normally distributed; and by counts and percentages for categorical variables with confidence intervals (CI) for important outcomes. To assess the association of VTE with continuous variables such as age, we used independent samples T-tests with appropriate transformations for not normally distributed data. To examine relationships between VTE incidence and categorical variables, we used Chi-square analysis, the Fisher’s exact test when expected counts were less than 5, or we calculated odds ratios (OR) with 95% CI. We assessed the association between the duration of prophylactic anticoagulation (after a natural logarithm transformation) and SCL characteristics with analysis variance (ANOVA). We determined statistical significance at P < 0.05 and performed all statistical analyses with SPSS v 27 (IBM Corp., Armonk, NY, USA).

2.4 Ethical consideration

The ethics committee of the Rehabilitation Medical Center approved the study (approval number 003-13-LOE) and waived the requirement to obtain informed consent from the patients because the study was retrospective and investigators anonymized the data before analysis.

3.1 Participants

Of 1,298 persons admitted to the department during the 10-year study period, 221 suffered from conditions other than SCL, such as Guillain-Barré syndrome or low back pain disability, 266 were admitted to rehabilitation more than 3 months after SCL onset, and 1 was younger than 18 years. Of the remaining 810, who conformed to the inclusion/exclusion criteria, we excluded 93 because they were less than 1 week in rehabilitation, and 32 because data about the anticoagulation received or follow-up for one year after SCL onset were missing. Six hundred eighty-five men and women were included in the final analysis. Of these, 666 arrived at rehabilitation without a VTE diagnosis. Table 1 shows patient characteristics.

VTE was diagnosed in 37 patients, 5.4%, of all participants (95% CI 3.7–7.1%). Eighteen patients (2.6%) had a diagnosis of DVT, 17 (2.5%) of PE, and 2 (0.3%) of both DVT and PE. Clinical DVT diagnosis was verified by ultrasound at least in 65% of the patients, and clinical PE diagnosis by pulmonary CT-angiography at least in 58%.

Of the VTE diagnoses, 19 had been made before admission to rehabilitation, 9 after admission but before discharge, and 9 after discharge but within 1 year from SCL onset. Of the 18 (2.7%) patients who contracted VTE after admission to rehabilitation, 12 patients (1.8%) had a diagnosis of DVT, 5 (0.75%) of PE, and 1 (0.15%) of both DVT and PE. Sixteen of the 18 who contracted VTE after admission to rehabilitation amounted to 3% (95% CI 1.6–4.5%) of the patients who received preventive anticoagulation during rehabilitation. Table 2 details the characteristics of persons who contracted VTE.

Figure 1 shows the time from SCL onset to VTE. In 11 participants (29.7% of all the patients with VTE and 61% of those diagnosed after admission), VTE occurred 3 months or more after SCL onset (in all of them after the admission). Of them, 4 had an AIS grade A, 1 B, 3 C, and 3 D. None of them walked without aids at admission, and 1 was walking without aids 3 months after SCL onset. The SCL level was above C5 in 2 of them, T7-T12 in 8, and below L2 in 1. Eight of the 11 (73%) had risk factors other than the SCL, such as active cancer (Anderson & Spencer, 2003), severe infection (Crous-Bou et al., 2016), previous VTE (Anderson & Spencer, 2003; Piran & Schulman, 2016), chronic kidney disease (Wattanakit & Cushman, 2009), hip surgery (Anderson & Spencer, 2003; Galson, 2008), or drug abuse (Coull et al., 2021). Of the 26 patients who contracted VTE within 3 months of SCL onset, 1 had an AIS grade A, 2 B, 6 C, and 17 D. Two of them walked without aids at admission, and 5 were walking without aids 3 months after SCL onset. The SCL level was above C5 in 10 of them, C5-C8 in 2, T1-T6 in 2, T7-T12 in 2, and below L2 in 10. Only 4 of the 26 (15%) had additional risk factors (P = 0.001). Two of them had active cancer, and 2 had a previous VTE. Of the 7 patients who contracted VTE within 3 months of SCL onset but after admission, 1 (14%) had additional risk factors.

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Fig. 1

Time from SCL onset to VTE diagnosis (months). Dark gray represents individuals with risk factors for VTE other than SCL. Light gray represents individuals with no documented risk factors.

Of the 11 participants who contracted VTE 3 months or more after SCL onset, in 10 VTE occurred despite preventive anticoagulation, lasting 3.7–9.3 weeks, 35–262 days after discontinuing it, either at rehabilitation (3 patients) or after discharge. Of the 11, 8 patients received prophylactic anticoagulation with Enoxaparin 40 mg/day, 1 with Enoxaparin 60 mg/day and 1 was treated with Coumadin.

LOS was 89±55 days for the patients without a VTE diagnosis in the first year after SCL onset, compared with 103±61 days for all the patients with a VTE diagnosis after SCL onset (P > 0.1), and 118±53 days for the patients who contracted VTE after admission to rehabilitation (P < 0.04).

Thirteen patients (1.9% of those included in the study) died within a year from SCL onset. Causes of death were infection (n = 7), cancer (n = 1), and PE (n = 1). The person who died after contracting clinically diagnosed PE was a 58-year-old woman with advanced cancer. She received preventive enoxaparin until 6.5 weeks after SCL onset, and PE occurred after discharge from rehabilitation, and 8.5 months after SCL onset. The cause of death of 4 individuals is unknown, but all of them suffered from medical problems in addition to the SCL.

3.4 VTE risk factors

In the entire group of included individuals, as well as among the patients admitted to rehabilitation without a VTE diagnosis, those with former VTE were more likely to develop DVT or PE (OR = 8.6, 95% CI = 2.5–29.4; OR = 14.2, 95% CI = 3.5–57.8, respectively). Among the patients admitted to rehabilitation without a VTE diagnosis, VTE occurred in 5.1%, 7.1%, 4.6%, and 1.4%, in patients with AIS grades A, B, C, or D, respectively. The SCL level of the patients with AIS grades A–C was cervical in 35.9%, thoracic in 35.9%, and lumbar in 28.2%. In those with D, 45.4%, 15.4%, and 39.2%, respectively. The VTE risk was higher in those with AIS grades A–C than in those with grade D (OR = 3.8, 95% CI = 1.4–10.1). VTE risk was lower in patients who were walking with or without aids (OR = 0.14, 95% CI = 0.02–1.06, P = 0.026) and higher in patients with thoracic lesions (P = 0.022). However, both not-walking and thoracic level of lesion were associated with the AIS grades A–C (P < 0.001).

In all the patients, as well as in those admitted to rehabilitation without a VTE diagnosis, we found no significant relationships between VTE incidence and age, gender, BMI > 30, traumatic or non-traumatic etiology, or spinal surgery (P > 0.1, Tables 1 2).

3.5 Prophylactic anticoagulant therapy

Of the 666 patients who arrived at rehabilitation without a VTE diagnosis, 526 (79%) received preventive anticoagulation during inpatient rehabilitation (some of them at therapeutic doses). As shown in Table 3, 480 (72%) received low-dose enoxaparin (≤60 mg/day), most commonly 40 mg/day. Enoxaparin prevention ended before discharge from inpatient rehabilitation for 97% of the patients receiving it. Enoxaparin at higher doses (≥80 mg/day), heparin, warfarin, or direct oral anticoagulants (DOACs) were prescribed for 46 patients (6.9%), 87% of whom had comorbidities such as atrial fibrillation. Ninety-four percent of the individuals treated with warfarin or DOACs were instructed to continue taking those medications after discharge, probably because of comorbidities. Of the 18 patients who contracted VTE during or after inpatient rehabilitation, 15 (83.3%) received preventive enoxaparin (most commonly 40 mg/day), 1 (5.6%) received warfarin for prevention, and 2 (11.1%) did not receive prophylactic anticoagulation, one because of good mobility at admission and the other because of relative contraindication for anticoagulation.

In 4 of the 16 patients who received preventive anticoagulation and contracted VTE after admission, VTE occurred during anticoagulation, and in 12, 7–262 days after its discontinuation.

Table 3 also shows that 140 people with SCL (21%) did not receive preventative anticoagulation during rehabilitation. Reasons were a good level of mobility or strong muscle power (n = 92, 65.7%) more than 4–6 weeks from the onset of SCL or surgery to admission to rehabilitation (n = 34, 24.3%), medical reasons (n = 8, 5.7%), refusal of suggested treatment, (n = 3, 2.1%), and lack of contribution of the SCL to the decrease in mobility (n = 3, 2.1%). The difference in VTE incidence between the patients who received (3%) or did not receive (1.4%) preventive anticoagulation was non-significant (OR 2.2 95% CI 0.5–9.6).

Prophylactic anticoagulation at rehabilitation started on the first day after admission in 94.7% of patients; only in 1.7% of patients it started 7–68 days after admission. The median duration of prophylactic anticoagulation during rehabilitation was 4.6 weeks (25% –75% percentiles = 3.1–6.6), and it continued until a median period of 6.4 weeks after SCL onset or spinal surgery (25% –75% percentiles = 5.8–9.7). Figure 2 demonstrates the duration of prophylactic anticoagulation during rehabilitation. Patients with AIS grades A–C received prophylaxis for 5.9 (4.1–8.6) weeks and those with grade D for 4.1 (2.7–5.3) weeks (P < 0.001) Lesion level did not affect the duration of preventive anticoagulation (P > 0.7). The average duration of preventative anticoagulation was 5 weeks for patients who contracted VTE and 5.6 weeks for those who did not (P > 0.4).

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Fig. 2

Duration (weeks) of prophylactic therapy during impatient rehabilitation. Light gray bars represent patient with AIS grades A–C; dark gray bars represent patients with AIS grade D. The figure refers to patients admitted without a VTE diagnosis.

Side effects were recorded for 8 of the 526 patients who received preventive anticoagulation during SCL rehabilitation (1.5%, 95% CI 0.5–2.6%) as shown in Table 4. Seven patients (1.3%) had clinically significant bleeding and one (0.2%) had a diagnosis of thrombocytopenia. Of the major bleeding events and thrombocytopenia after SCL onset, 6 occurred following enoxaparin and 2 could be attributed to warfarin or DOACs, administered because of a spinal thrombus or atrial fibrillation (Table 4).

4.1 Main findings

The main findings of this study show that VTE prophylaxis in the investigated spinal rehabilitation department was effective relative to historic VTE rates without prophylaxis, but limited. In this study, VTE incidence in the patients who received preventive anticoagulation after arriving at rehabilitation was much lower than it may have been without anticoagulation, and it was not fatal in patients whose SCL was the only VTE risk factor (Dhall et al., 2013; Fujii et al., 1992; Wei et al., 2023). VTE at rehabilitation prolonged LOS, however, and the present prophylaxis was insufficient. More than 5% of all the SCL patients who arrived at rehabilitation and 3% of those who received preventive anticoagulation in rehabilitation still contracted VTE, which was fatal in a patient with an additional risk factor, despite the preventive measures.

VTE and mortality percentages presented here are, respectively, compatible with rates described previously for persons with SCL or following surgery, who received preventive anticoagulation (Arnold et al., 2017; Junqueira et al., 2017), or for patients at elevated risk of VTE, who received preventive anticoagulation and who contracted PE (Bělohlávek et al., 2013; Klemen et al., 2020; Søgaard et al.,2014).

4.2 Possible shortcomings of the anticoagulation regimen used

Several possible shortcomings of the anticoagulation regimen used may have contributed to limiting the reduction in VTE rate. These include lack of prophylactic anticoagulation in certain patients, short duration, inadequate dose, and inadequate attention paid to VTE risk factors.

4.3 Recommendation

Based on our findings and the above discussion, we recommend conducting a prospective study aimed at assessing the efficacy and safety of:

Starting or continuing preventive enoxaparin for all SCL patients arriving to rehabilitation without a contra-indication for anticoagulation immediately after admission. This is the earliest start possible in rehabilitation, although it may not comply with the recommendation to start prophylaxis within 72 hours of SCL onset (Aito et al., 2002).

We expect the suggested enoxaparin regimen to reduce VTE incidence, with a limited increase in bleeding. We also expect that administering enoxaparin to all SCL patients arriving in rehabilitation without a contra-indication, with the suggested doses, timing for starting and discontinuing it, and the adjustment to VTE risk factors will improve the efficacy of prophylaxis.

In addition to seeking ways of improving LMWH VTE prevention, studies are needed to test the safety and efficacy of DOACs for preventive anticoagulation (Weidner et al., 2020 If DOACs prove at least as safe and effective for this purpose as LMWH, they may provide more convenient VTE prophylaxis.

4.4 Study limitations

As a result of the retrospective nature of the study, information on VTE incidence and prophylaxis before admission to rehabilitation is missing, and in many cases, documentation of objective VTE imaging was not found. Nevertheless, there is no reason to assume that VTE incidence was lower in patients who were not referred to the studied rehabilitation department, and a rate of 3–5%, probably represents the minimal VTE incidence after SCL in the entire study population. Objective VTE imaging for PE and DVT was documented in 58% and 65% of patients, respectively, and in the patients without it, the clinical diagnosis would have been confirmed in at least an additional 14% and 21% (Line, 2001; Markel et al., 1995). This means that at least 72% and 86% of the VTE diagnoses were solid, and VTE incidence after SCL and standard anticoagulation remains considerable, higher than bleeding, and warrants the prospective study we recommend.