Prevention of postoperative deep venous thrombosis and pulmonary emboli with combined modalities

M Borow, H J Goldson

PMID: 6195948

Abstract

Worldwide statistics reveal that 25 to 40 per cent of patients who are over the age of 40 years and operated on for 1 or more hours will develop a deep venous thrombosis (DVT). The studies reviewed in this paper were performed to evaluate several modalities and compare their effectiveness in preventing DVT in postoperative patients. In the first study, five modalities plus a control group were evaluated in 562 patients from five surgical specialties. The incidence of DVT in the control group was 35 per cent. Though most of the pharmacologic agents were effective in reducing the incidence of DVT, the antistasis devices (gradient elastic stockings and intermittent pneumatic compression) were most effective. The purpose of the second study was to evaluate the effectiveness of combining a pharmacologic drug with an antistasis modality. Deep venous thrombosis was virtually eliminated in this group of 328 patients. There was only a 1.5 per cent incidence of DVT in the treated population as compared to a 26.8 per cent incidence in the control group. Thus, it seems that combining one antistasis and one pharmacologic agent greatly reduces the incidence of lower extremity thrombi. I-125 fibrinogen scanning was the most sensitive test in detecting DVT and had an accuracy of 97 per cent.

Reference: Am Surg 1983 Nov;49(11):599-605.

Patterns of Failure of a Standardized Perioperative Venous Thromboembolism Prophylaxis Protocol

Michael R Cassidy ¹, Ryan D Macht ¹, Pamela Rosenkranz ¹, Joseph A Caprini ², David McAneny ³

Affiliations expand

PMID: 26821972. DOI: 10.1016/j.jamcollsurg.2015.12.022

Abstract

Background: Venous thromboembolism (VTE) is a leading contributor to morbidity after operations. We previously implemented a standardized VTE risk assessment, based on the Caprini score, along with risk-stratified prophylaxis. This system reduced the odds ratio of a VTE event from 3.02 to 0.75. We investigated patterns of failure to determine characteristics of patients in whom VTE develops despite the protocol.

Methods: We reviewed all nontrauma general surgery patients with evidence of VTE after the inception of a VTE risk assessment and prophylaxis program. Characteristics were recorded, including demographics, diagnoses, operations, risk profile, prophylaxis prescribed, and regimen compliance.

Results: Twenty-seven patients failed the protocol and manifested VTE, representing an overall VTE rate of 0.3%. Of these patients, 63% had emergency operations and 52% underwent multiple operations, compared with 13% and 2.0% of the nontrauma general surgery population in whom VTE did not develop, respectively (p < 0.001). Of patients with VTE, 52% had pre-existing or postoperative infections, 22% had malignancies, but only 15% had missed 1 or more doses of pharmacologic prophylaxis during hospitalization. Five VTEs manifested after discharge; one of those patients was prescribed extended prophylaxis beyond hospitalization, and an extended course was not provided to 3 who were eligible. One patient had underestimation of the Caprini score due to lack of awareness of a family history of VTE.

Conclusions: Emergency and multiple operations seem to confer dramatic hazards for VTE, despite standard prophylaxis. These factors are not currently captured in the Caprini model, but might be significant modifiers of risk that should prompt reassessment, perhaps with a weighted numeric value along with enhanced prophylaxis. It is encouraging that most patients received appropriate prophylaxis in compliance with the protocol.

Reference:

J Am Coll Surg 2016 Jun;222(6):1074-80. doi: 10.1016/j.jamcollsurg.2015.12.022.Epub 2015 Dec 24.

Implementation and Validation of the 2013 Caprini Score for Risk Stratification of Arthroplasty Patients in the Prevention of Venous Thrombosis

Eugene S Krauss ¹, Ayal Segal ¹, MaryAnne Cronin ², Nancy Dengler ¹, Martin L Lesser ³, Seungjun Ahn ³, Joseph A Caprini ^{2 4}

PMID: 30939898. PMCID: PMC6714918. DOI: 10.1177/1076029619838066

Erratum in Corrigendum.

[No authors listed]Clin Appl Thromb Hemost. 2019 Jan-Dec;25:1076029619851962. doi: 10.1177/1076029619851962.PMID: 31099256 Free PMC article. No abstract available.

Abstract

Appropriate chemoprophylaxis choice following arthroplasty requires accurate patient risk assessment. We compared the results of our prospective department protocol to the Caprini risk assessment model (RAM) retrospectively in this study group. Our goal was to determine whether the department protocol or the Caprini score would identify venous thromboembolism (VTE) events after total joint replacement. A secondary purpose was to validate the 2013 Caprini RAM in joint arthroplasty and determine whether patients with VTE would be accurately identified using the Caprini score. A total of 1078 patients met inclusion criteria. A Caprini score of 10 or greater is considered high risk and a score of 9 or less is considered low risk. The 2013 version of the Caprini RAM retrospectively stratified 7 of the 8 VTE events correctly, while only 1 VTE was identified with the prospective department protocol. This tool provided a consistent, accurate, and efficacious method for risk stratification and selection of chemoprophylaxis.

Reference:

Clin Appl Thromb Hemost. Jan-Dec 2019;25:1076029619838066.doi: 10.1177/1076029619838066.

Frequency and Risk Factor of Lower-limb Deep Vein Thrombosis after Major Orthopedic Surgery in Vietnamese Patients

My Hanh Bui ¹, Duong Duc Hung ², Pham Quang Vinh ³, Nguyen Hoang Hiep ⁴, Le Lan Anh ³, Toi Chu Dinh ³

PMID: 32215072. PMCID: PMC7084020. DOI: 10.3889/oamjms.2019.369

Abstract

Background: Deep venous thrombosis (DVT) is a prevalent complication of orthopedic surgery. According in many studies. The incidence of DVT may be up to 50% if thromboprophylaxis is not available.

Aim: The objective of this study was to check the degree of disease, clinical characteristics and analyzed factors in vulnerabilities with lower-limp DVT after orthopedic surgery in a Vietnam teaching hospital.

Methods: Orthopedic patients who met criteria were recruited at our hospital between August 2017 and June 2018. Ultrasound was used to discovering lower-limp DVT in pre-surgery and 7 days after surgery in all patients.

Results: The incidence of DVT after orthopedic surgery was 7.2%. Patients with older age (> 60) have a risk of 2 times higher of DVT after surgery than normal people (p < 0.05). The incidence of postoperative DVT was higher in immobile individuals > 72 hours (p < 0.05). Patients with prolonged surgical time (>120 minutes) had a higher risk of postoperative DVT than non-surgical patients’ surgery (p < 0.05).

Conclusions: DVT remains a common complication following orthopedic surgery. Older age, immobility status, and surgical time have been found to be risky factors for the development of postoperative lower-limp DVT in orthopedic patients.

Reference:

Maced J Med Sci. 2019 Dec 20;7(24):4250-4254. doi: 10.3889/oamjms.2019.369.eCollection 2019 Dec 30.

Usefulness of clinical predictors for preoperative screening of deep vein thrombosis in hip fractures

Kitchai Luksameearunothai ^1 2, Paphon Sa-Ngasoongsong ³, Noratep Kulachote ¹, Sorawut Thamyongkit ^1 4, Praman Fuangfa ⁵, Pongsthorn Chanplakorn ¹, Patarawan Woratanarat ¹, Chanyut Suphachatwong ¹

PMID: 28532441. PMCID: PMC5440897. DOI: 10.1186/s12891-017-1582-5

Abstract

Background: Recent studies showed that preoperative deep vein thrombosis (DVT) was common after hip fracture (HF), and preoperative DVT screening has been recommended for preventing the fatal DVT-related complications, especially in elderly HF patients with high surgical risk. However, to our knowledge, no previous studies have demonstrated the correlation between the clinical risk predictors and preoperative DVT. Therefore, this study aimed to correlate those clinical predictors related to DVT risk assessment with the incidence of preoperative DVT.

Methods: A prospective study was conducted, between July 2015 and June 2016, in 92 HF patients. All patients were evaluated for the DVT-related risk, as patients’ characteristics, clinical signs, D-dimer, DVT risk assessment score (Wells score and Caprini score), and then underwent doppler ultrasonography preoperatively. The incidence of preoperative DVT was correlated with each clinical risk predictor, and then significant factors were calculated for diagnostic accuracy.

Results: The average patients’ age was 78 ± 10 years. Sixty-eight patients (74%) were female. The incidence of preoperative DVT was 16.3% (n = 15). The median time from injury to doppler ultrasonography was 2 days (range 0-150 days). DVT group showed a significantly higher in Wells score and Caprini score compared to the non-DVT group (p < 0.05 all). Sensitivity and specificity of Wells score ≥ 2 and Caprini score ≥12 were 47 and 81, and 93 and 35%, respectively.

Conclusion: DVT risk assessment may be helpful for stratifying the risk of preoperative DVT in elderly HFs. Those with Caprini score ≥ 12 should be screened with doppler ultrasonography preoperatively. Those with Wells score 0-1 had low risk for preoperative DVT, so the surgery could perform without delay.

Reference:

BMC Musculoskelet Disord. 2017 May 22;18(1):208.doi: 10.1186/s12891-017-1582-5.

Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis

E F W van Vlijmen ¹, S Wiewel-Verschueren ^1 2, T B M Monster ³, K Meijer ¹

PMID: 27121914. DOI: 10.1111/jth.13349

Abstract

Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a natural anticoagulant deficiency. Contrary, additive risk of factor V Leiden (FVL) or prothrombin-G20210A (PT) mutation is modest. Women with a FVL/PT-mutation as single risk factor can use COCs if alternatives are not tolerated.

Summary: Background Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), which is shown to be more pronounced in women with hereditary thrombophilia. Currently, WHO recommendations state that COC-use in women with hereditary thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden and prothrombin-G20210A mutation) is associated with an unacceptable health risk. Objective To perform a meta-analysis evaluating the additional risk of VTE in COC-users with thrombophilia. Methods The MEDLINE and EMBASE databases were searched on 10 February 2015 for potential eligible studies. A distinction was made between ‘mild’ (factor V Leiden and prothrombin-G20210A mutation) and ‘severe’ thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). Results We identified 12 case-control and three cohort studies. In COC-users, mild and severe thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95% confidence interval [CI], 4.21-8.23) and 7-fold (RR, 7.15; 95% CI, 2.93-17.45), respectively. The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). Conclusion These results support discouraging COC-use in women with severe hereditary thrombophilia. By contrast, additive VTE risk of mild thrombophilia is modest. When no other risk factors are present, (e.g. family history) COCs can be offered to these women when reliable alternative contraceptives are not tolerated.

Reference:

J Thromb Haemost. 2016 Jul;14(7):1393-403. doi: 10.1111/jth.13349.Epub 2016 Jun 16.

Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis

Bernardine H Stegeman ¹, Marcos de Bastos, Frits R Rosendaal, A van Hylckama Vlieg, Frans M Helmerhorst, Theo Stijnen, Olaf M Dekkers

PMID: 24030561. PMCID: PMC3771677. DOI: 10.1136/bmj.f5298

Abstract

Objective: To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.

Design: Systematic review and network meta-analysis.

Data sources: PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013.

Review methods: Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables.

Results: 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10,000 woman years, in line with previously reported incidences of 1-6 per 10,000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.

Conclusion: All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.

Reference:

BMJ. 2013 Sep 12;347:f5298. doi: 10.1136/bmj.f5298.

Mechanisms of estrogen-induced venous thromboembolism

Svetlana N Tchaikovski ¹, Jan Rosing

PMID: 20163835. DOI: 10.1016/j.thromres.2010.01.045

Abstract

The use of oral contraceptives (OC) is a well established risk factor for venous thrombosis. It has been known for many years that almost all haemostatic parameters i.e. plasma levels of coagulation factors, anticoagulant proteins and proteins involved in the fibrinolytic pathway change during OC use. The discovery of several risk factors of venous thrombosis in the 1990s shed new light on the association between the effects of OC on the haemostatic system and the increased risk of venous thrombosis. In this review, we summarize the current knowledge on the effects of different kinds of hormonal contraceptives (OC, transdermal contraceptives, vaginal ring and levonorgestrel-releasing intrauterine device) on haemostatic variables and the relationship between the changes of these variables and the risk of venous thrombosis.

Reference:

Thromb Res. 2010 Jul;126(1):5-11. doi: 10.1016/j.thromres.2010.01.045.Epub 2010 Feb 16.

Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases

Yana Vinogradova ¹, Carol Coupland ², Julia Hippisley-Cox ²

PMID: 30626577. PMCID: PMC6326068. DOI: 10.1136/bmj.k4810

Erratum in

• Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.

[No authors listed]BMJ. 2019 Jan 15;364:l162. doi: 10.1136/bmj.l162.PMID: 30647094 Free PMC article. No abstract available.

Abstract

Objective: To assess the association between risk of venous thromboembolism and use of different types of hormone replacement therapy.

Design: Two nested case-control studies.

Setting: UK general practices contributing to the QResearch or Clinical Practice Research Datalink (CPRD) databases, and linked to hospital, mortality, and social deprivation data.

Participants: 80 396 women aged 40-79 with a primary diagnosis of venous thromboembolism between 1998 and 2017, matched by age, general practice, and index date to 391 494 female controls.

Main outcome measures: Venous thromboembolism recorded on general practice, mortality, or hospital records. Odds ratios were adjusted for demographics, smoking status, alcohol consumption, comorbidities, recent medical events, and other prescribed drugs.

Results: Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date. Of these two groups, 4915 (85%)and 16 938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Estradiol had a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01).

Conclusions: In the present study, transdermal treatment was the safest type of hormone replacement therapy when risk of venous thromboembolism was assessed. Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations

Thromboprophylaxis in Pregnancy

Diana Kolettis ¹, Sabrina Craigo ²

PMID: 29747737. DOI: 10.1016/j.ogc.2018.01.007

Abstract

Venous thromboembolism is a leading cause of maternal morbidity and mortality worldwide. Identifying women who are at greatest risk for venous thromboembolism, and managing their pregnancies with appropriate thromboprophylaxis is essential to decreasing this life-threatening condition. Those at greatest risk are patients with thrombophilias, a personal or family history of venous thromboembolism, and those undergoing cesarean delivery. Current international guidelines on thromboprophylaxis vary in details, but all strategies rely on risk factor identification and thromboprophylaxis for the highest risk patients. All guidelines require clinicians to think critically about individual patient’s risk factors throughout pregnancy and the postpartum period.

Keywords: Pregnancy; Prophylaxis; Thromboembolism; Thromboprophylaxis.

Reference:

Obstet Gynecol Clin North Am. 2018 Jun;45(2):389-402. doi: 10.1016/j.ogc.2018.01.007.

Persistent antiphospholipid antibody (aPL) in asymptomatic carriers as a risk factor for future thrombotic events: a nationwide prospective study

P Mustonen ¹, K V Lehtonen ², K Javela ³, M Puurunen ⁴

PMID: 25164304. DOI: 10.1177/0961203314545410

Abstract

Objectives: The long-term prognosis of individuals fulfilling the laboratory criteria, but not clinical criteria, of antiphospholipid syndrome (APS) has not been widely investigated. The primary aim of this study was to evaluate the incidence of first thrombotic event (deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), stroke or transient ischaemic attack (TIA) in a nationwide antiphospholipid antibody (aPL) carrier cohort.

Design: We conducted a prospective nationwide cohort study.

Setting: The aPL profile of participants was recorded from the laboratory database. Information was collected about thrombotic and pregnancy complications, subsequent medical history, other risk factors for thrombosis, use of prophylactic antithrombotic medication and general health.

Participants: Participants included adult asymptomatic aPL carriers recognized in Finland during 1971-2009.

Main outcome measure: The main outcome measure was incidence of first thrombotic event.

Results: A total of 119 (89% female) aPL carriers were followed for mean (SD) of 9.1 (7.5) years (range 3-41 years). Sixty-one per cent of the study participants had autoimmune disease, most often systemic lupus erythematosus (SLE). Thirty-six of 119 (30%) were either double or triple positive, 56% single lupus anticoagulant (LA) positive, and 8% and 5% single anticardiolipin antibodies (aCL) and anti-β2glycoprotein I antibodies (aβ2GPI) positive, respectively. Nine (7.6%) study patients experienced a first thrombotic event (five DVT, one PE, two MI, one TIA) mean (SD) 7.2 (8.3) years (range 1-26 years) after aPL detection (annual incidence rate 0.8%). All individuals who developed thrombotic complications had autoimmune disease. Annual rate of first thrombotic event in carriers of single positivity (0.65%) was equal to the known risk of thrombosis in the healthy Caucasian population, whereas the rate was two times higher in carriers of double or triple positivity (1.27%). Sixteen of 79 (20%) women experienced pregnancy complications.

Conclusions: Double or triple positivity for aPL is a risk factor for future thrombotic events, especially in individuals with an underlying autoimmune disease, whereas single positivity does not seem to carry an elevated risk of thrombosis.

Keywords: Antiphospholipid antibodies; anticardiolipin antibodies; lupus anticoagulant; thrombosis; β2-glycoprotein I antibodies.

Reference:

2014 Dec;23(14):1468-76. doi: 10.1177/0961203314545410. Epub 2014 Aug 27.

Incidence of venous thromboembolism in patients undergoing surgical treatment for malignancy by type of neoplasm: An analysis of ACS-NSQIP data from 2005 to 2010

Caroline E Reinke ¹, Giorgos C Karakousis, Rachel A Hadler, Jeffrey A Drebin, Douglas L Fraker, Rachel R Kelz

PMID: 22828139. DOI: 10.1016/j.surg.2012.05.003

Abstract

Introduction: This study investigates the incidence, relative risk, and adjusted odds ratio of venous thromboembolism (VTE) among patients with malignant neoplasms compared with those with benign neoplasms, as well as the incidence of outpatient VTE diagnosis.

Methods: We performed a retrospective cohort study of patients in the ACS-NSQIP database from 2005 to 2010 with a postoperative diagnosis of neoplasm. The incidence of 30-day VTE, post-VTE death, the incidence of postdischarge VTE diagnosis, and the relative risk of postoperative VTE was calculated by cancer site. Logistic regression was used to calculate an independent odds ratio for each neoplasm site, adjusting for age, gender, body mass index, and operative time.

Results: Of 208,200 patients, 159,752 had a malignant diagnosis of the sites of interest and 48,448 had benign/carcinoma in situ neoplasms. The incidence, relative risk, and odds ratio of 30-day VTE varied substantially by site of malignancy. The absolute incidence of outpatient VTE diagnosis varied by site and percent of VTE diagnosed as an outpatient was found to increase over time.

Conclusion: Recommendations for VTE prophylaxis and duration of VTE prophylaxis for patients undergoing operations may benefit from tailoring to the specific type of malignancy. The increasing percentage of VTE events diagnosed as an outpatient may impact hospitals substantially as financial penalties for readmission are enacted.

Reference:

Surgery. 2012 Aug;152(2):186-92. doi: 10.1016/j.surg.2012.05.003.

Incidence of venous thromboembolism and its effect on survival among patients with common cancers

Helen K Chew ¹, Theodore Wun, Danielle Harvey, Hong Zhou, Richard H White

PMID: 16505267. DOI: 10.1001/archinte.166.4.458

Abstract

Background: The incidence of venous thromboembolism after diagnosis of specific cancers and the effect of thromboembolism on survival are not well defined.

Methods: The California Cancer Registry was linked to the California Patient Discharge Data Set to determine the incidence of venous thromboembolism among cancer cases diagnosed between 1993 and 1995. The incidence and timing of thromboembolism within 1 and 2 years of cancer diagnosis and the risk factors associated with thromboembolism and death were determined.

Results: Among 235 149 cancer cases, 3775 (1.6%) were diagnosed with venous thromboembolism within 2 years, 463 (12%) at the time cancer was diagnosed and 3312 (88%) subsequently. In risk-adjusted models, metastatic disease at the time of diagnosis was the strongest predictor of thromboembolism. Expressed as events per 100 patient-years, the highest incidence of thromboembolism occurred during the first year of follow-up among cases with metastatic-stage pancreatic (20.0), stomach (10.7), bladder (7.9), uterine (6.4), renal (6.0), and lung (5.0) cancer. Adjusting for age, race, and stage, diagnosis of thromboembolism was a significant predictor of decreased survival during the first year for all cancer types (hazard ratios, 1.6-4.2; P<.01).

Conclusions: The incidence of venous thromboembolism varied with cancer type and was highest among patients initially diagnosed with metastatic-stage disease. The incidence rate of thromboembolism decreased over time. Diagnosis of thromboembolism during the first year of follow-up was a significant predictor of death for most cancer types and stages analyzed. For some types of cancer, the incidence of thromboembolism was sufficiently high to warrant prospective clinical trials of primary thromboprophylaxis.

Reference:

Arch Intern Med. 2006 Feb 27;166(4):458-64. doi: 10.1001/archinte.166.4.458.

Central venous catheters and upper extremity deep vein thrombosis in medical inpatients: the Medical Inpatients and Thrombosis (MITH) Study

J P Winters ¹, P W Callas ¹, M Cushman ¹, A B Repp ¹, N A Zakai ¹

PMID: 26340226. DOI: 10.1111/jth.13131

Abstract

Background: Upper extremity deep vein thrombosis (UEDVT) is an increasingly recognized complication in medical inpatients, with few data available regarding the incidence, risk factors and association with central venous catheter (CVC) use.

Methods: Between 2002 and 2009 all cases of hospital-acquired venous thromboembolism (VTE) at a university hospital were frequency matched 1 : 2 to non-cases without VTE by admission year and medical service. Records were abstracted to identify, characterize and assess risk factors for UEDVT. Weighted logistic regression was used to calculate odds ratios (ORs) for UEDVT associated with use of a CVC, adjusting for known VTE risk factors.

Results: Two hundred and ninety-nine cases of VTE complicated 64 034 admissions to medical services (4.6 per 1000 admissions). UEDVT constituted 51% (91/180) of all deep vein thrombosis (DVT), for an incidence of 1.4 per 1000 admissions (95% confidence interval [CI], 0.8-1.7). There were 247 CVCs placed per 1000 admissions (95% CI, 203-292). The use of a CVC was associated with a 14.0-fold increased risk of UEDVT (95% CI, 5.9-33.2), but was not associated with a significantly increased risk of PE (OR, 1.3; 95% CI, 0.8-2.1). Peripherally inserted central catheters had a higher OR for UEDVT (OR, 13.0; 95% CI, 6.1-27.6) than centrally inserted central venous catheters (CICC) (OR, 3.4; 95% CI, 1.7-6.8).

Conclusion: UEDVT is a relevant complication affecting medical inpatients, accounting for half of hospital-acquired DVTs. Use of CVCs was strongly associated with risk of UEDVT.

Reference:

J Thromb Haemost. 2015 Dec;13(12):2155-60. doi: 10.1111/jth.13131. Epub 2015 Oct 27.

Risk of venous thromboembolism associated with totally implantable venous access ports in cancer patients: A systematic review and meta-analysis

Meng Jiang ¹, Chang-Li Li ², Chun-Qiu Pan ³, Xin-Wu Cui ¹, Christoph F Dietrich ⁴

PMID: 32479699. DOI: 10.1111/jth.14930

Abstract

Background: Totally implantable venous access ports (TIVAPs) for chemotherapy are associated with venous thromboembolism (VTE). We aimed to quantify the incidence of TIVAP-associated VTE and compare it with external central venous catheters (CVCs) in cancer patients through a meta-analysis.

Methods: Studies reporting on VTE risk associated with TIVAP were retrieved from medical literature databases. In publications without a comparison group, the pooled incidence of TIVAP-related VTE was calculated. For studies comparing TIVAPs with external CVCs, odds ratios (ORs) were calculated to assess the risk of VTE.

Results: In total, 80 studies (11 with a comparison group and 69 without) including 39 148 patients were retrieved. In the noncomparison studies, the overall symptomatic VTE incidence was 2.76% (95% confidence interval [CI]: 2.24-3.28), and 0.08 (95 CI: 0.06-0.10) per 1000 catheter-days. This risk was highest when TIVAPs were inserted via the upper-extremity vein (3.54%, 95% CI: 2.94-4.76). Our meta-analysis of the case-control studies showed that TIVAPs were associated with a decreased risk of VTE compared with peripherally inserted central catheters (OR = 0.20, 95% CI: 0.09-0.43), and a trend for lower VTE risk compared with Hickman catheters (OR = 0.75, 95% CI: 0.37-1.50). Meta-regression models suggested that regional difference may significantly impact on the incidence of VTE associated with TIVAPs.

Conclusions: Current evidence suggests that the cancer patients with TIVAP are less likely to develop VTE compared with external CVCs. This should be considered when choosing the indwelling intravenous device for chemotherapy. However, more attention should be paid when choosing upper-extremity veins as the insertion site.

Reference:

J Thromb Haemost. 2020 Sep;18(9):2253-2273. doi: 10.1111/jth.14930.Epub 2020 Jul 15.

Postoperative venous thrombosis. Evaluation of five methods of treatment

M Borow, H Goldson

PMID: 6161550. DOI: 10.1016/0002-9610(81)90168-9

Abstract

Five methods for preventing deep venous thrombosis in postoperative patients were evaluated and compared with a control group. Five hundred patients from five surgical specialties were studied. The incidence of deep venous thrombosis was 37.3 percent in the control group but significantly less within all treatment groups. The minidose heparin group had the highest incidence (26.9 percent) because there were a large number of bilateral thromboses. The antistasis modalities did slightly better than the drugs; the intermittent pneumatic compression group had the fewest thromboses (11.9 percent). The significant risk factors for postoperative deep venous thrombosis are (1) obesity, (2) malignancy, (3) a history of venous disease, major surgery or major fracture, (4) length of surgery greater than 1 hour, and (5) increasing age. Four nonfatal pulmonary emboli occurred in 500 patients. Two were in women with hysterectomies in whom thrombosis had never been detected in an extremity; it is presumed that these clots arose from pelvic veins. It is thus recommended that patients in these high risk groups be treated prophylactically with one of the aforementioned modalities to decrease the risk of postoperative deep venous thrombosis. Of the different methods used to detect deep venous thrombosis, iodine-125 fibrinogen scanning was superior to both impedance plethysmography and venous Doppler ultrasound. One hundred percent of the thrombi were identified with scanning, whereas far fewer were detected with the latter methods. It is recommended that fibrinogen scanning be used clinically in patients in high risk categories who are undergoing major operative procedures.

Reference:

Am J Surg. 1981 Feb;141(2):245-51. doi: 10.1016/0002-9610(81)90168-9.

Efficacy of extended thrombo-prophylaxis in major abdominal surgery: what does the evidence show? A meta-analysis

Federico Jorge Bottaro ¹, Maria Cristina Elizondo, Carlos Doti, Julio Enrique Bruetman, Pablo Diego Perez Moreno, Eduardo Oscar Bullorsky, Jose Manuel Ceresetto

Affiliations expand

PMID: 18521515. DOI: 10.1160/TH07-12-0759

Abstract

Venous thromboembolism (VTE) is a frequent complication following major abdominal surgery. The use of low-molecular-weight heparins (LMWH) to prevent thrombotic events in these patients is a common and well documented practice. However, there is some controversy surrounding the duration of the prophylaxis, as it has been suggested that the risk persists for several weeks after surgery. The objective of this meta-analysis is to systematically review the clinical studies that compared safety and efficacy of extended use of LMWH (for three to four weeks after surgery) versus conventional in-hospital prophylaxis. An electronic data base search was performed. Only randomized, controlled studies were eligible. Data on the incidence of deep vein thrombosis (DVT), VTE and bleeding were extracted. Only three studies fulfilled the inclusion criteria. The indication for surgery was neoplastic disease in 70.6% (780/1104) of patients. The administration of extended LMWH prophylaxis significantly reduced the incidence of VTE, 5.93% (23/388) versus 13.6% (55/405), RR 0.44 (CI 95% 0.28 – 0.7); DVT 5.93% (23/388) versus 12.9% (52/402), RR 0.46 (CI 95% 0.29 – 0.74); proximal DVT 1% (4/388) versus 4.72% (19/402), RR 0.24 (CI 95% 0.09 – 0.67). We found no significant difference in major or minor bleeding between the two groups: 3.85% (21/545) in the extended thrombo-prophylaxis (ETP) group versus 3.48% (19/559) in the conventional prophylaxis group; RR 1.12 (CI 95% 0.61 – 2.06). There was no heterogeneity between the studies. We conclude that ETP with LMWH should be considered as a safe and useful strategy to prevent VTE in high-risk major abdominal surgery.

Reference:

Thromb Haemost. 2008 Jun;99(6):1104-11. doi: 10.1160/TH07-12-0759.

The value of family history as a risk indicator for venous thrombosis

Irene D Bezemer ¹, Felix J M van der Meer, Jeroen C J Eikenboom, Frits R Rosendaal, Carine J M Doggen

PMID: 19307525. DOI: 10.1001/archinternmed.2008.589

Abstract

Background: A positive family history of venous thrombosis may reflect the presence of genetic risk factors. Once a risk factor has been identified, it is not known whether family history is of additional value in predicting an individual’s risk. We studied the contribution of family history to the risk of venous thrombosis in relation to known risk factors.

Methods: In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis, a population-based case-control study, we collected blood samples and information about family history and environmental triggers from 1605 patients with a first venous thrombosis and 2159 control subjects.

Results: A total of 505 patients (31.5%) and 373 controls (17.3%) reported having 1 or more first-degree relatives with a history of venous thrombosis. A positive family history increased the risk of venous thrombosis more than 2-fold (odds ratio [95% confidence interval], 2.2 [1.9-2.6]) and up to 4-fold (3.9 [2.7-5.7]) when more than 1 relative was affected. Family history corresponded poorly with known genetic risk factors. Both in those with and without genetic or environmental risk factors, family history remained associated with venous thrombosis. The risk increased with the number of factors identified; for those with a genetic and environmental risk factor and a positive family history, the risk was about 64-fold higher than for those with no known risk factor and a negative family history.

Conclusions: Family history is a risk indicator for a first venous thrombosis, regardless of the other risk factors identified. In clinical practice, family history may be more useful for risk assessment than thrombophilia testing.

Reference:

Arch Intern Med. 2009 Mar 23;169(6):610-5. doi: 10.1001/archinternmed.2008.589.

Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden

Bengt Zöller ¹, Henrik Ohlsson, Jan Sundquist, Kristina Sundquist

PMID: 23348971. DOI: 10.1160/TH12-10-0743

Erratum in

Thromb Haemost. 2013 Jul 1;110(1):204

Abstract

Venous thromboembolism (VTE) clusters in families, but the familial risk of VTE has only been determined in first-degree relatives. This nationwide study aimed to determine the familial risk of VTE in first-, second- and third-degree relatives of affected individuals. The Swedish Multi-Generation Register was linked to Hospital Discharge Register data for the period 1987-2009. This was a case-cohort study. Odds ratios (ORs) for VTE were calculated for individuals whose relatives were hospitalised for VTE, as determined by the International Classification of Diseases (ICD), and those whose relatives were unaffected by VTE. The familial OR for VTE was 2.49 in siblings (95% confidence interval [CI] 2.40-2.58), 2.65 in children (2.50-2.80), 2.09 in parents (2.03-2.15), 1.52 in maternal half-siblings (1.26-1.85), 2.34 in paternal half-siblings (2.00-2.73), 1.69 in nieces/nephews (1.57-1.82), 1.47 in cousins (1.33-1.64), and 1.14 in spouses of individuals diagnosed with VTE (1.09-1.18). Familial clustering was stronger at young ages. The familial transmission was slightly stronger for males compared with females but was only significant for siblings 1.13 (1.05-1.22) and parents 1.11 (1.05-1.78) of probands. The present data showing an increased VTE risk among not only first-degree relatives but also second- and third-degree relatives indicate that the genetic component of the familial clustering of VTE is strong. Family history is a potentially useful genetic surrogate marker for clinical VTE risk assessment, even in second- and third degree-relatives.

Reference:

Thromb Haemost. 2013 Mar;109(3):458-63. doi: 10.1160/TH12-10-0743. Epub 2013 Jan 24.

Hypercoagulability Is a Stronger Risk Factor for Ischaemic Stroke than for Myocardial Infarction: A Systematic Review

Alberto Maino ¹, Frits R Rosendaal ², Ale Algra ³, Flora Peyvandi ⁴, Bob Siegerink ⁵

PMID: 26252207. PMCID: PMC4529149. DOI: 10.1371/journal.pone.0133523

Abstract

Background and purpose: Hypercoagulability increases the risk of arterial thrombosis; however, this effect may differ between various manifestations of arterial disease.

Methods: In this study, we compared the effect of coagulation factors as measures of hypercoagulability on the risk of ischaemic stroke (IS) and myocardial infarction (MI) by performing a systematic review of the literature. The effect of a risk factor on IS (relative risk for IS, RRIS) was compared with the effect on MI (RRMI) by calculating their ratio (RRR = RRIS/RRMI). A relevant differential effect was considered when RRR was >1+ its own standard error (SE) or <1-SE.

Results: We identified 70 publications, describing results from 31 study populations, accounting for 351 markers of hypercoagulability. The majority (203/351, 58%) had an RRR greater than 1. A larger effect on IS risk than MI risk (RRE>1+1SE) was found in 49/343 (14%) markers. Of these, 18/49 (37%) had an RRR greater than 1+2SE. On the opposite side, a larger effect on MI risk (RRR<1-1SE) was found in only 17/343 (5%) markers.

Conclusions: These results suggest that hypercoagulability has a more pronounced effect on the risk of IS than that of MI.

Reference:

PLoS One. 2015 Aug 7;10(8):e0133523. doi: 10.1371/journal.pone.0133523.eCollection 2015.

Venous Thromboembolism: Genetics and Thrombophilias

Manila Gaddh ¹, Rachel P Rosovsky ²

PMID: 33694139. DOI: 10.1055/s-0041-1723937

Abstract

Venous thromboembolism (VTE) is a major cause of morbidity and mortality throughout the world. Up to one half of patients who present with VTE will have an underlying thrombophilic defect. This knowledge has led to a widespread practice of testing for such defects in patients who develop VTE. However, identifying a hereditary thrombophilia by itself does not necessarily change outcomes or dictate therapy. Furthermore, family history of VTE by itself can increase an asymptomatic person’s VTE risk several-fold, independent of detecting a known inherited thrombophilia. In this article, we will describe the current validated hereditary thrombophilias including their history, prevalence, and association with VTE. With a focus on evaluating both risks and benefits of testing, we will also explore the controversies of why, who, and when to test as well as discuss contemporary societal guidelines. Lastly, we will share how these tests have been integrated into clinical practice and how to best utilize them in the future.

Reference:

Semin Respir Crit Care Med. 2021 Apr;42(2):271-283. doi: 10.1055/s-0041-1723937.Epub 2021 Mar 10.

Hereditary thrombophilia

Astrit Dautaj ¹, Geraldo Krasi, Vilma Bushati, Vincenza Precone, Miriam Gheza, Francesco Fioretti, Marianna Sartori, Alisia Costantini, Sabrina Benedetti, Matteo Bertelli

PMID: 31577252. PMCID: PMC7233636. DOI: 10.23750/abm.v90i10-S.8758

Abstract

Thrombophilia is a group of disorders in which blood has an increased tendency to clot. It may be caused by inherited or acquired conditions. Thrombophilia is associated with risk of deep venous thrombosis and/or venous thromboembolism. Factor V Leiden thrombophilia is the most common inherited form of thrombophilia and prothrombin-related thrombophilia is the second most common genetic form of thrombophilia, occurring in about 1.7-3% of the European and US general populations (3). Thrombophilia may have autosomal dominant, autosomal recessive or X-linked inheritance. Genetic testing is useful for confirming diagnosis and for differential diagnosis, recurrence risk evaluation and asymptomatic diagnosis in families with a known mutation.

Reference:

Acta Biomed. 2019 Sep 30;90(10-S):44-46. doi: 10.23750/abm.v90i10-S.8758.

Venous thromboembolism rates remained unchanged in operative lower extremity orthopaedic trauma patients from 2008 to 2016

Jared A Warren ¹, Kavin Sundaram ², Robert Hampton ³, Damien Billow ⁴, Brendan Patterson ⁵, Nicolas S Piuzzi ⁶

PMID: 31519436. DOI: 10.1016/j.injury.2019.09.003

Abstract

Background: Venous thromboembolism (VTE) is a serious complication that contributes to morbidity, mortality, and healthcare costs during the surgical care of patient with lower extremity fractures. Despite this, few recommendations on the topic exist and the literature on VTE incidence is incomplete. Therefore, this study will attempt to estimate annual incidence and trends in 30-day thrombotic events and mortality for the following fractures: (1) hip, (2) femur, (3) patella, (4) tibia and/or fibula, and (5) ankle.

Methods: We identified 120,521 operative lower extremity orthopaedic trauma patients from 2008 to 2016 using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. To evaluate the relationship between the year in which surgery was performed and comorbidities and demographic information bivariate analysis was performed. Bivariate analysis was also performed for the outcomes of interest and year in which the surgery was performed to assess for change. Additionally, bimodal multivariate logistic regression models for hip, femur, and ankle fractures were built, comparing the years 2009 to 2016 using 2008 as a baseline.

Results: Overall incidence for VTE over the study period was 1.7% for hip fractures, 2.4% for femur fractures, 0.9% for patella fractures, 1.1% in tibia and/or fibula fractures, and 0.6% in ankle fractures. Over the study period VTE incidence saw a significant decrease (p < 0.05) in hip and femur fractures, but not for patella, tibia and/or fibula, and ankle fractures. After adjusting for confounding factors with multivariate analysis, the change in hip and femur fractures was no longer significant, while no significant decrease was again found for ankle fractures (p > 0.05).

Conclusion: Our study demonstrates that VTE rates have remained unchanged in operative lower extremity orthopaedic trauma from 2008 to 2016. This highlights the need for higher quality evidence on this important topic in orthopaedic trauma, including a reevaluation on the necessity of thromboprophylaxis guidelines.

Reference:

Injury. 2019 Oct;50(10):1620-1626. doi: 10.1016/j.injury.2019.09.003. Epub 2019 Sep 4.

Venous thromboembolism after severe trauma: incidence, risk factors and outcome

Thomas Paffrath ¹, Arasch Wafaisade, Rolf Lefering, Christian Simanski, Bertil Bouillon, Timo Spanholtz, Sebastian Wutzler, Marc Maegele, Trauma Registry of DGU

PMID: 19608183. DOI: 10.1016/j.injury.2009.06.010

Abstract

Background: Venous thromboembolic events (VTEs) are common life-threatening complications after trauma, but epidemiology and reported risk factors still vary. The purpose of this investigation was to determine the incidence of VTEs among hospitalised trauma patients, to identify potential risk factors and to assess whether their presence was associated with: (a) the magnitude and pattern of injury, (b) therapeutic interventions and (c) outcome, all by using a large population-based registry.

Patients and methods: Patient data from the Trauma Registry of the German Society for Trauma Surgery (TR-DGU) including datasets from more than 35,000 trauma patients were screened for all clinically relevant VTEs, i.e. deep vein thrombosis (DVT) and pulmonary embolism (PE). A total of 7937 patients were identified for further investigation and multivariate logistic regression analyses were performed to assess potential risk factors for VTEs and to evaluate the effect of VTEs on outcome.

Results: One hundred forty-six of 7937 patients developed clinically relevant VTEs during post-traumatic hospitalisation corresponding to an overall incidence rate of 1.8%. Two-thirds (97/146) of all VTEs occurred during the first 3 weeks after admission. At the time point of the event 118/146 (80.8%) patients were under either mechanical or chemical prophylaxis. Multivariate analysis with VTE as dependent variable identified injury severity score, the number of operative procedures, pelvic injury (abbreviated injury scale > or = 2) and concomitant diseases (i.e. diabetes, renal failure, malignancies and congenital or acquired coagulation disorders) as independent risk factors. The presence of VTEs was associated with higher frequencies of sepsis (25% vs. 9.1%), single (63.6% vs. 41.3%) and multiple organ failure (49% vs. 25%) and prolonged in-hospital length of stay (52+/-34 days vs. 29+/-30 days; all p<0.001). The mortality in the VTE group totaled 13.7% vs. 7.4% in the non-VTE group (p=0.004). The presence of PE was associated with a mortality rate of 25.7%. The adjusted odds ratio of post-traumatic VTEs for hospital mortality was 2.08 (CI95 1.15-3.78; p=0.016).

Conclusion: The occurrence of clinically apparent VTEs during post-traumatic hospitalisation is low but associated with increased morbidity and mortality. Conclusions about the effectiveness of different thromboprophylactic measures could not be drawn, since detailed information was not recorded. However, 80.8% of VTE patients had received thromboprophylaxis at the time point of the event.

Reference:

Injury. 2010 Jan;41(1):97-101. doi: 10.1016/j.injury.2009.06.010.

An economic evaluation of venous thromboembolism prophylaxis strategies in critically ill trauma patients at risk of bleeding

T Carter Chiasson ¹, Braden J Manns, Henry Thomas Stelfox

PMID: 19554085. PMCID: PMC2695771. DOI: 10.1371/journal.pmed.1000098

Abstract

Background: Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.

Methods and findings: Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies-pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF) — in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.

Conclusions: The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs.

Ref:

PLoS Med. 2009 Jun 23;6(6):e1000098. doi: 10.1371/journal.pmed.1000098. Epub 2009 Jun 23.

Venous thromboembolism after spinal cord injury

Robert W Teasell ¹, Jane T Hsieh, Jo-Anne L Aubut, Janice J Eng, Andrei Krassioukov, Linh Tu, Spinal Cord Injury Rehabilitation Evidence Review Research Team

PMID: 19236977. PMCID: PMC3104991. DOI: 10.1016/j.apmr.2008.09.557

Abstract

Objective: To review systematically the published literature on the treatment of deep venous thromboembolism after spinal cord injury (SCI).

Data sources: MEDLINE/PubMed, CINAHL, EMBASE, and PsycINFO databases were searched for articles addressing the treatment of deep venous thromboembolism post-SCI. Randomized controlled trials (RCTs) were assessed for methodologic quality using the Physiotherapy Evidence Database Scale, while non-RCTs were assessed using the Downs and Black evaluation tool.

Study selection: Studies included RCTs, non-RCTS, cohort, case-control, case series, pre-post, and postinterventional studies. Case studies were included only when no other studies were available.

Data extraction: Data extracted included demographics, the nature of the study intervention, and study results.

Data synthesis: Levels of evidence were assigned to the interventions using a modified Sackett scale.

Conclusions: Twenty-three studies met inclusion criteria. Thirteen studies examined various pharmacologic interventions for the treatment or prevention of deep venous thrombosis in patients with SCI. There was strong evidence to support the use of low-molecular-weight heparin in reducing venous thrombosis events, and a higher adjusted dose of unfractionated heparin was found to be more effective than 5000 units administered every 12 hours, although bleeding complications were more common. Nonpharmacologic treatments were also reviewed, but again limited evidence was found to support these treatments.

Reference:

Arch Phys Med Rehabil. 2009 Feb;90(2):232-45. doi: 10.1016/j.apmr.2008.09.557.

Prevention of Venous Thromboembolism in Individuals with Spinal Cord Injury: Clinical Practice Guidelines for Health Care Providers, 3rd ed.: Consortium for Spinal Cord Medicine

No authors listed

PMID: 29339863. PMCID: PMC4981016. DOI: 10.1310/sci2203-209

See full article for guidelines.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981016/

Reference:

Top Spinal Cord Inj Rehabil. Summer 2016;22(3):209-240. doi: 10.1310/sci2203-209.